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Integration of dietary nutrition and TRIB3 action into diabetes mellitus.
Lu G;Li J;Gao T;Liu Q;Chen O;Zhang X;Xiao M;Guo Y;Wang J;Tang Y;Gu J
Academic Journal Academic Journal | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0376405 Publication Model: Print Cited Medium: Internet ISSN: 1753-4887 (Electronic) Linking ISSN: 00296643 NLM ISO Abbreviation: Nutr Rev Subsets: MEDLINE Please log in to see more details
Despite intensive studies for decades, the common mechanistic correlations among the u... more
Integration of dietary nutrition and TRIB3 action into diabetes mellitus.
Publisher: Oxford University Press Country of Publication: United States NLM ID: 0376405 Publication Model: Print Cited Medium: Internet ISSN: 1753-4887 (Electronic) Linking ISSN: 00296643 NLM ISO Abbreviation: Nutr Rev Subsets: MEDLINE
Despite intensive studies for decades, the common mechanistic correlations among the underlying pathology of diabetes mellitus (DM), its complications, and effective clinical treatments remain poorly characterized. High-quality diets and nutrition therapy have played an indispensable role in the management of DM. More importantly, tribbles homolog 3 (TRIB3), a nutrient-sensing and glucose-responsive regulator, might be an important stress-regulatory switch, linking glucose homeostasis and insulin resistance. Therefore, this review aimed to introduce the latest research progress on the crosstalk between dietary nutrition intervention and TRIB3 in the development and treatment of DM. This study also summarized the possible mechanisms involved in the signaling pathways of TRIB3 action in DM, in order to gain an in-depth understanding of dietary nutrition intervention and TRIB3 in the pathogenesis of DM at the organism level.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Subject terms:

Humans - Cell Cycle Proteins metabolism - Insulin metabolism - Glucose metabolism - Diet - Repressor Proteins metabolism - Protein Serine-Threonine Kinases genetics - Protein Serine-Threonine Kinases metabolism - Protein Serine-Threonine Kinases antagonists & inhibitors - Diabetes Mellitus

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Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex.
Nguyen DM;Rath DH;Devost D;Pétrin D;Rizk R;Ji AX;Narayanan N;Yong D;Zhai A;...
Academic Journal Academic Journal | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE Please log in to see more details
Heterotrimeric G proteins can be regulated by posttranslational modifications, includi... more
Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex.
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain, engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3 KCTD5 ) that ubiquitylates Gβγ and reduces Gβγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3 NTD /Gβ 1 γ 2 assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5 BTB /CUL3 NTD and KCTD5 CTD /Gβγ moieties of the structure. CRL3 KCTD5 engages the E3 ligase ARIH1 to ubiquitylate Gβγ in an E3-E3 superassembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1~ubiquitin conjugate reveals that some conformational states position the ARIH1~ubiquitin thioester bond to within 10 Å of lysine-23 of Gβ and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3 NTD /Gβγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex.
Competing Interests: Competing interests statement:The authors declare no competing interest.

Subject terms:

Protein Binding - Ubiquitination - Ubiquitin metabolism - Cullin Proteins genetics - Cullin Proteins metabolism - Ubiquitin-Protein Ligases metabolism - Carrier Proteins metabolism

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Calcium mediated static and dynamic allostery in S100A12: Implications for target recognition by S100 proteins.
Wang Q;DiForte C;Aleshintsev A;Elci G;Bhattacharya S;Bongiorno A;Gupta R
Academic Journal Academic Journal | Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE Please log in to see more details
Structure and functions of S100 proteins are regulated by two distinct calcium binding... more
Calcium mediated static and dynamic allostery in S100A12: Implications for target recognition by S100 proteins.
Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
Structure and functions of S100 proteins are regulated by two distinct calcium binding EF hand motifs. In this work, we used solution-state NMR spectroscopy to investigate the cooperativity between the two calcium binding sites and map the allosteric changes at the target binding site. To parse the contribution of the individual calcium binding events, variants of S100A12 were designed to selectively bind calcium to either the EF-I (N63A) or EF-II (E31A) loop, respectively. Detailed analysis of the backbone chemical shifts for wildtype protein and its mutants indicates that calcium binding to the canonical EF-II loop is the principal trigger for the conformational switch between 'closed' apo to the 'open' Ca 2+ -bound conformation of the protein. Elimination of binding in S100-specific EF-I loop has limited impact on the calcium binding affinity of the EF-II loop and the concomitant structural rearrangement. In contrast, deletion of binding in the EF-II loop significantly attenuates calcium affinity in the EF-I loop and the structure adopts a 'closed' apo-like conformation. Analysis of experimental amide nitrogen ( 15 N) relaxation rates (R 1 , R 2 , and 15 N-{ 1 H} NOE) and molecular dynamics (MD) simulations demonstrate that the calcium bound state is relatively floppy with pico-nanosecond motions induced in functionally relevant domains responsible for target recognition such as the hinge domain and the C-terminal residues. Experimental relaxation studies combined with MD simulations show that while calcium binding in the EF-I loop alone does not induce significant motions in the polypeptide chain, EF-I regulates fluctuations in the polypeptide in the presence of bound calcium in the EF-II loop. These results offer novel insights into the dynamic regulation of target recognition by calcium binding and unravels the role of cooperativity between the two calcium binding events in S100A12.
(© 2024 The Protein Society.)

Subject terms:

Calcium metabolism - Protein Conformation - Calcium-Binding Proteins chemistry - EF Hand Motifs - Peptides metabolism - S100 Proteins chemistry - S100A12 Protein metabolism

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Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
Busto JV;Ganesan I;Mathar H;Steiert C;Schneider EF;Straub SP;Ellenrieder L;...
Academic Journal Academic Journal | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE Please log in to see more details
The majority of mitochondrial precursor proteins are imported through the Tom40 β-barr... more
Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE
The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAM Mco6 complex for the biogenesis of the mitochondrial outer membrane.
Competing Interests: Declaration of interests U.S. is an employee and shareholder of Logopharm GmbH. B.F. is a founder and scientific advisor of Logopharm GmbH.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Subject terms:

Mitochondrial Precursor Protein Import Complex Proteins - Mitochondrial Membrane Transport Proteins genetics - Mitochondrial Membrane Transport Proteins metabolism - Membrane Proteins genetics - Membrane Proteins metabolism - Saccharomyces cerevisiae metabolism - Mitochondrial Proteins genetics - Mitochondrial Proteins metabolism - Carrier Proteins metabolism - Protein Transport - Membrane Transport Proteins metabolism - Saccharomyces cerevisiae Proteins genetics - Saccharomyces cerevisiae Proteins metabolism

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14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway.
Mukherjee S;Roy S;Mukherjee S;Harikishore A;Bhunia A;Mandal AK
Academic Journal Academic Journal | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE Please log in to see more details
The cAMP/PKA and mitogen-activated protein kinase (MAPK) signaling cascade control man... more
14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway.
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
The cAMP/PKA and mitogen-activated protein kinase (MAPK) signaling cascade control many cellular processes and are highly regulated for optimal cellular responses upon external stimuli. Phosphodiesterase 8A (PDE8A) is an important regulator that inhibits signaling via cAMP-dependent PKA by hydrolyzing intracellular cAMP pool. Conversely, PDE8A activates the MAPK pathway by protecting CRAF/Raf1 kinase from PKA-mediated inhibitory phosphorylation at Ser259 residue, a binding site of scaffold protein 14-3-3. It still remains enigmatic as to how the cross-talk involving PDE8A regulation influences cAMP/PKA and MAPK signaling pathways. Here, we report that PDE8A interacts with 14-3-3ζ in both yeast and mammalian system, and this interaction is enhanced upon the activation of PKA, which phosphorylates PDE8A's Ser359 residue. Biophysical characterization of phospho-Ser359 peptide with 14-3-3ζ protein further supports their interaction. Strikingly, 14-3-3ζ reduces the catalytic activity of PDE8A, which upregulates the cAMP/PKA pathway while the MAPK pathway is downregulated. Moreover, 14-3-3ζ in complex with PDE8A and cAMP-bound regulatory subunit of PKA, RIα, delays the deactivation of PKA signaling. Our results define 14-3-3ζ as a molecular switch that operates signaling between cAMP/PKA and MAPK by associating with PDE8A.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Subject terms:

Humans - Mitogen-Activated Protein Kinases metabolism - Phosphorylation - Phosphoserine metabolism - Cyclic AMP-Dependent Protein Kinase RIalpha Subunit metabolism - 14-3-3 Proteins metabolism - 3',5'-Cyclic-AMP Phosphodiesterases metabolism - Cyclic AMP-Dependent Protein Kinases metabolism - MAP Kinase Signaling System

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Excess phosphate promotes SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation via the SCAP‑SREBP2 signaling pathway.
Liu MH;Lin XL;Xiao LL
Academic Journal Academic Journal | Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE Please log in to see more details
Hyperphosphatemia or severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infe... more
Excess phosphate promotes SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation via the SCAP‑SREBP2 signaling pathway.
Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE
Hyperphosphatemia or severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can promote cardiovascular adverse events in patients with chronic kidney disease. Hyperphosphatemia is associated with elevated inflammation and sterol regulatory element binding protein 2 (SREBP2) activation, but the underlying mechanisms in SARS‑CoV‑2 that are related to cardiovascular disease remain unclear. The present study aimed to elucidate the role of excess inorganic phosphate (PI) in SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and the underlying mechanisms in vascular smooth muscle cells (VSMCs). The expression levels of SARS‑CoV‑2 N protein, SREBP cleavage‑activating protein (SCAP), mature N‑terminal SREBP2, NLRP3, procaspase‑1, cleaved caspase‑1, IL‑1β and IL‑18 were examined by western blotting. The expression levels of SREBP2, HMG‑CoA reductase, HMGCS1, low density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), SREBP1c, fatty acid synthase, stearyl coenzyme A desaturase 1, acetyl‑CoA carboxylase α and ATP‑citrate lyase were determined by reverse transcription‑quantitative PCR. The translocation of SCAP or NLRP3 from the endoplasmic reticulum to the Golgi was detected by confocal microscopy. The results showed that excess PI promoted SCAP‑SREBP and NLRP3 complex translocation to the Golgi, potentially leading to NLRP3 inflammasome activation and lipogenic gene expression. Furthermore, PI amplified SARS‑CoV‑2 N protein‑induced inflammation via the SCAP‑SREBP pathway, which facilitates NLRP3 inflammasome assembly and activation. Inhibition of phosphate uptake with phosphonoformate sodium alleviated NLRP3 inflammasome activation and reduced SREBP‑mediated lipogenic gene expression in VSMCs stimulated with PI and with SARS‑CoV‑2 N protein overexpression. Inhibition of SREBP2 or small interfering RNA‑induced silencing of SREBP2 effectively suppressed the effect of PI and SARS‑CoV‑2 N protein on NLRP3 inflammasome activation and lipogenic gene expression. In conclusion, the present study identified that PI amplified SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and lipogenic gene expression via the SCAP‑SREBP signaling pathway.

Subject terms:

Humans - Inflammasomes metabolism - NLR Family, Pyrin Domain-Containing 3 Protein genetics - NLR Family, Pyrin Domain-Containing 3 Protein metabolism - Proprotein Convertase 9 metabolism - Sterol Regulatory Element Binding Protein 2 genetics - Sterol Regulatory Element Binding Protein 2 metabolism - SARS-CoV-2 metabolism - Phosphates - Sterol Regulatory Element Binding Protein 1 metabolism - Signal Transduction - Inflammation - Hyperphosphatemia - COVID-19 - Membrane Proteins - Intracellular Signaling Peptides and Proteins

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The muscle protein synthetic response following corn protein ingestion does not differ from milk protein in healthy, young adults.
Pinckaers PJM;Weijzen MEG;Houben LHP;Zorenc AH;Kouw IWK;de Groot LCPGM;Verd...
Academic Journal Academic Journal | Publisher: Springer-Verlag Country of Publication: Austria NLM ID: 9200312 Publication Model: Electronic Cited Medium: Internet ISSN: 1438-2199 (Electronic) Linking ISSN: 09394451 NLM ISO Abbreviation: Amino Acids Subsets: MEDLINE Please log in to see more details
Plant-derived proteins are generally believed to possess lesser anabolic properties wh... more
The muscle protein synthetic response following corn protein ingestion does not differ from milk protein in healthy, young adults.
Publisher: Springer-Verlag Country of Publication: Austria NLM ID: 9200312 Publication Model: Electronic Cited Medium: Internet ISSN: 1438-2199 (Electronic) Linking ISSN: 09394451 NLM ISO Abbreviation: Amino Acids Subsets: MEDLINE
Plant-derived proteins are generally believed to possess lesser anabolic properties when compared with animal-derived proteins. This is, at least partly, attributed to the lower leucine content of most plant-derived proteins. Corn protein has a leucine content that is highest among most plant-derived proteins and it even exceeds the levels observed in animal-derived proteins such as whey protein. Therefore, this study aimed to compare muscle protein synthesis rates following the ingestion of 30 g corn protein and a 30 g blend of corn plus milk protein with 30 g milk protein. In a randomized, double blind, parallel-group design, 36 healthy young males (26 ± 4 y) received primed continuous L-[ring- 13 C 6 ]-phenylalanine infusions and ingested 30 g corn protein (CORN), 30 g milk protein (MILK), or a 30 g proteinblend with 15 g corn plus 15 g milk protein (CORN + MILK). Blood and muscle biopsies were collected for 5 h following protein ingestion to assess post-prandial plasma amino acid profiles and myofibrillar protein synthesis rates. The results show that Ingestion of protein increased myofibrillar protein synthesis rates from basal post-absorptive values in all treatments(P < 0.001). Post-prandial myofibrillar protein synthesis rates did not differ between CORN vs MILK (0.053 ± 0.013 vs 0.053 ± 0.013%∙h -1 , respectively; t-test P = 0.90), or between CORN + MILK vs MILK (0.052 ± 0.024 vs 0.053 ± 0.013%∙h -1 , respectively; t-test P = 0.92). Ingestion of 30 g corn protein, 30 g milk protein, or a blend of 15 g corn plus 15 g milk protein robustly increases muscle protein synthesis rates in young males. The muscle protein synthetic response to the ingestion of 30 g corn-derived protein does not differ from the ingestion of an equivalent amount of milk protein in healthy, young males. Clinical Trial Registry number. NTR6548 (registration date: 27-06-2017) https://www.trialregister.nl/ .
(© 2024. The Author(s).)

Subject terms:

Male - Dietary Proteins metabolism - Eating - Leucine metabolism - Muscle, Skeletal metabolism - Plant Proteins metabolism - Zea mays metabolism - Humans - Young Adult - Adult - Milk Proteins - Muscle Proteins metabolism

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A Yeast Modular Cloning (MoClo) Toolkit Expansion for Optimization of Heterologous Protein Secretion and Surface Display in Saccharomyces cerevisiae .
O'Riordan NM;Jurić V;O'Neill SK;Roche AP;Young PW
Academic Journal Academic Journal | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101575075 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2161-5063 (Electronic) Linking ISSN: 21615063 NLM ISO Abbreviation: ACS Synth Biol Subsets: MEDLINE Please log in to see more details
Saccharomyces cerevisiae is an attractive host for the expression of secreted proteins... more
A Yeast Modular Cloning (MoClo) Toolkit Expansion for Optimization of Heterologous Protein Secretion and Surface Display in Saccharomyces cerevisiae .
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101575075 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2161-5063 (Electronic) Linking ISSN: 21615063 NLM ISO Abbreviation: ACS Synth Biol Subsets: MEDLINE
Saccharomyces cerevisiae is an attractive host for the expression of secreted proteins in a biotechnology context. Unfortunately, many heterologous proteins fail to enter, or efficiently progress through, the secretory pathway, resulting in poor yields. Similarly, yeast surface display has become a widely used technique in protein engineering but achieving sufficient levels of surface expression of recombinant proteins is often challenging. Signal peptides (SPs) and translational fusion partners (TFPs) can be used to direct heterologous proteins through the yeast secretory pathway, however, selection of the optimal secretion promoting sequence is largely a process of trial and error. The yeast modular cloning (MoClo) toolkit utilizes type IIS restriction enzymes to facilitate an efficient assembly of expression vectors from standardized parts. We have expanded this toolkit to enable the efficient incorporation of a panel of 16 well-characterized SPs and TFPs and five surface display anchor proteins into S. cerevisiae expression cassettes. The secretion promoting signals are validated by using five different proteins of interest. Comparison of intracellular and secreted protein levels reveals the optimal secretion promoting sequence for each individual protein. Large, protein of interest-specific variations in secretion efficiency are observed. SP sequences are also used with the five surface display anchors, and the combination of SP and anchor protein proves critical for efficient surface display. These observations highlight the value of the described panel of MoClo compatible parts to allow facile screening of SPs and TFPs and anchor proteins for optimal secretion and/or surface display of a given protein of interest in S. cerevisiae .

Subject terms:

Recombinant Proteins metabolism - Protein Transport - Protein Sorting Signals genetics - Cloning, Molecular - Saccharomyces cerevisiae genetics - Saccharomyces cerevisiae metabolism - Saccharomyces cerevisiae Proteins genetics - Saccharomyces cerevisiae Proteins metabolism

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A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53.
Zoltsman G;Dang TL;Kuchersky M;Faust O;Silva MS;Ilani T;Wentink AS;Bukau B;...
Academic Journal Academic Journal | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE Please log in to see more details
J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a... more
A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53.
Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE
J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 Elsevier Inc. All rights reserved.)

Subject terms:

Humans - Molecular Chaperones genetics - Molecular Chaperones metabolism - HSP70 Heat-Shock Proteins metabolism - Protein Folding - Tumor Suppressor Protein p53 genetics - Tumor Suppressor Protein p53 metabolism - Neoplasms

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Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.
Li H;Ji Z;Paulo JA;Gygi SP;Rapoport TA
Academic Journal Academic Journal | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE Please log in to see more details
Most eukaryotic proteins are degraded by the 26S proteasome after modification with a ... more
Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.
Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE
Most eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1. Rad23 and Ubx5 stimulate polyubiquitin binding to the 26S proteasome and the Cdc48-UN complex, respectively, allowing these machines to compete for substrates before and after their unfolding. Shp1 stimulates protein unfolding by the Cdc48-UN complex rather than substrate recruitment. Experiments in yeast cells confirm that many proteins undergo bidirectional substrate shuttling between the 26S proteasome and Cdc48 ATPase before being degraded.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Subject terms:

Animals - Proteolysis - Saccharomyces cerevisiae genetics - Saccharomyces cerevisiae metabolism - Polyubiquitin metabolism - Adenosine Triphosphatases genetics - Adenosine Triphosphatases metabolism - Valosin Containing Protein genetics - Valosin Containing Protein metabolism - Ubiquitin metabolism - Cell Cycle Proteins genetics - Cell Cycle Proteins metabolism - Mammals metabolism - Proteasome Endopeptidase Complex metabolism - Saccharomyces cerevisiae Proteins genetics - Saccharomyces cerevisiae Proteins metabolism

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Phase separation of GRP7 facilitated by FERONIA-mediated phosphorylation inhibits mRNA translation to modulate plant temperature resilience.
Xu F;Wang L;Li Y;Shi J;Staiger D;Yu F
Academic Journal Academic Journal | Publisher: Cell Press Country of Publication: England NLM ID: 101465514 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1752-9867 (Electronic) Linking ISSN: 16742052 NLM ISO Abbreviation: Mol Plant Subsets: MEDLINE Please log in to see more details
Changes in ambient temperature profoundly affect plant growth and performance. Therefo... more
Phase separation of GRP7 facilitated by FERONIA-mediated phosphorylation inhibits mRNA translation to modulate plant temperature resilience.
Publisher: Cell Press Country of Publication: England NLM ID: 101465514 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1752-9867 (Electronic) Linking ISSN: 16742052 NLM ISO Abbreviation: Mol Plant Subsets: MEDLINE
Changes in ambient temperature profoundly affect plant growth and performance. Therefore, the molecular basis of plant acclimation to temperature fluctuation is of great interest. In this study, we discovered that GLYCINE-RICH RNA-BINDING PROTEIN 7 (GRP7) contributes to cold and heat tolerance in Arabidopsis thaliana. We found that exposure to a warm temperature rapidly induces GRP7 condensates in planta, which can be reversed by transfer to a lower temperature. Cell biology and biochemical assays revealed that GRP7 undergoes liquid-liquid phase separation (LLPS) in vivo and in vitro. LLPS of GRP7 in the cytoplasm contributes to the formation of stress granules that recruit RNA, along with the translation machinery component eukaryotic initiation factor 4E1 (eIF4E1) and the mRNA chaperones COLD SHOCK PROTEIN 1 (CSP1) and CSP3, to inhibit translation. Moreover, natural variations in GRP7 affecting the residue phosphorylated by the receptor kinase FERONIA alter its capacity to undergo LLPS and correlate with the adaptation of some Arabidopsis accessions to a wider temperature range. Taken together, our findings illustrate the role of translational control mediated by GRP7 LLPS to confer plants with temperature resilience.
(Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Subject terms:

Temperature - Phosphorylation - Phase Separation - RNA-Binding Proteins metabolism - Cold Temperature - Protein Biosynthesis - Arabidopsis Proteins genetics - Arabidopsis Proteins metabolism - Resilience, Psychological - Arabidopsis genetics - Arabidopsis metabolism

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Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.
Swint-Kruse L;Fenton AW
Academic Journal Academic Journal | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE Please log in to see more details
Advances in personalized medicine and protein engineering require accurately predictin... more
Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Advances in personalized medicine and protein engineering require accurately predicting outcomes of amino acid substitutions. Many algorithms correctly predict that evolutionarily-conserved positions show "toggle" substitution phenotypes, which is defined when a few substitutions at that position retain function. In contrast, predictions often fail for substitutions at the less-studied "rheostat" positions, which are defined when different amino acid substitutions at a position sample at least half of the possible functional range. This review describes efforts to understand the impact and significance of rheostat positions: (1) They have been observed in globular soluble, integral membrane, and intrinsically disordered proteins; within single proteins, their prevalence can be up to 40%. (2) Substitutions at rheostat positions can have biological consequences and ∼10% of substitutions gain function. (3) Although both rheostat and "neutral" (defined when all substitutions exhibit wild-type function) positions are nonconserved, the two classes have different evolutionary signatures. (4) Some rheostat positions have pleiotropic effects on function, simultaneously modulating multiple parameters (e.g., altering both affinity and allosteric coupling). (5) In structural studies, substitutions at rheostat positions appear to cause only local perturbations; the overall conformations appear unchanged. (6) Measured functional changes show promising correlations with predicted changes in protein dynamics; the emergent properties of predicted, dynamically coupled amino acid networks might explain some of the complex functional outcomes observed when substituting rheostat positions. Overall, rheostat positions provide unique opportunities for using single substitutions to tune protein function. Future studies of these positions will yield important insights into the protein sequence/function relationship.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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Amino Acid Sequence - Conserved Sequence - Evolution, Molecular - Intrinsically Disordered Proteins chemistry - Intrinsically Disordered Proteins genetics - Intrinsically Disordered Proteins metabolism - Membrane Proteins chemistry - Membrane Proteins genetics - Membrane Proteins metabolism - Protein Engineering - Structure-Activity Relationship - Humans - Amino Acid Substitution - Amino Acids genetics - Amino Acids metabolism - Proteins chemistry - Proteins genetics - Proteins metabolism

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Molecular Screening in Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: Anaplastic Lymphoma Kinase Analysis, Next-Generation Sequencing Fusion Gene Detection, and T-Cell Receptor Immunoprofiling.
Kalinova M;Mrhalova M;Kabickova E;Svaton M;Skotnicova A;Prouzova Z;Krenova ...
Academic Journal Academic Journal | Publisher: Elsevier Inc Country of Publication: United States NLM ID: 8806605 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0285 (Electronic) Linking ISSN: 08933952 NLM ISO Abbreviation: Mod Pathol Subsets: MEDLINE Please log in to see more details
Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) origina... more
Molecular Screening in Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: Anaplastic Lymphoma Kinase Analysis, Next-Generation Sequencing Fusion Gene Detection, and T-Cell Receptor Immunoprofiling.
Publisher: Elsevier Inc Country of Publication: United States NLM ID: 8806605 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0285 (Electronic) Linking ISSN: 08933952 NLM ISO Abbreviation: Mod Pathol Subsets: MEDLINE
Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) originates from the T-lineage and is marked by rearrangements of the ALK gene. More than 10 fusion partners with the ALK gene are known, with the most common being the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion. In 10% to 20% of the ALK+ ALCL cases, the ALK gene fuses with various other partners. Modern molecular techniques, especially next-generation sequencing (NGS), have eased the identification of ALK gene fusion partners and have allowed in-depth characterization of the T-cell receptor (TCR) repertoire. We devised a real-time quantitative reverse-transcription polymerase chain reaction to measure the expression of the translocated portion of the ALK gene. Fusion partners for the ALK gene were analyzed using rapid amplification of 5'cDNA ends (RACE) method or NGS. TCR immunoprofiling was performed by amplicon NGS. We studied 96 ALK+ ALCL patients. NPM1::ALK fusion gene was observed in 71 patients, ATIC::ALK in 9, and TPM3::ALK in 3. CLTC::ALK, MYH9::ALK, and RNF213::ALK fusions were identified in 2 patients each. We also discovered the TPM4::ALK and SATB1::ALK fusion genes, plus the following 2 previously unidentified ALK+ ALCL fusions: SQSTM1::ALK and CAPRIN1::ALK. High expression of the translocated ALK gene segment was observed in all 93 analyzed samples. TCR testing was conducted on 23 patients with available DNA. In 18 (78%) patients, we discerned at least one (ranging from 1 to 4) clonal TCR rearrangement. In 59% of the patients, clonal TCR beta junctions corresponded with sequences previously observed in both healthy donors and under various pathological conditions. Reverse-transcriptase quantitative detection of ALK expression is a fast and reliable method for both diagnosing and monitoring treatment response in ALK+ ALCL patients, irrespective of the ALK gene translocation. NGS reveals new ALK translocation partners. Both malignant and reactive TCR repertoires in ALK+ ALCL patients are unique and do not consistently occur among different patients.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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Humans - Anaplastic Lymphoma Kinase genetics - Receptor Protein-Tyrosine Kinases genetics - Protein-Tyrosine Kinases genetics - Translocation, Genetic - Transcription Factors genetics - Nuclear Proteins genetics - Receptors, Antigen, T-Cell genetics - High-Throughput Nucleotide Sequencing - Cell Cycle Proteins genetics - Adenosine Triphosphatases genetics - Lymphoma, Large-Cell, Anaplastic genetics - Lymphoma, Large-Cell, Anaplastic pathology - Matrix Attachment Region Binding Proteins - Ubiquitin-Protein Ligases

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Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer.
Li J;Zeng Q;Lin J;Huang H;Chen L
Academic Journal Academic Journal | Publisher: Springer Country of Publication: Japan NLM ID: 101239023 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1860-1499 (Electronic) Linking ISSN: 18601499 NLM ISO Abbreviation: Med Mol Morphol Subsets: MEDLINE Please log in to see more details
The relationship between the expression of the SATB2 and CDX2 proteins and common mole... more
Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer.
Publisher: Springer Country of Publication: Japan NLM ID: 101239023 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1860-1499 (Electronic) Linking ISSN: 18601499 NLM ISO Abbreviation: Med Mol Morphol Subsets: MEDLINE
The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.
(© 2023. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

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Humans - Proto-Oncogene Proteins B-raf genetics - DNA Mismatch Repair genetics - Proto-Oncogene Proteins p21(ras) genetics - Proto-Oncogene Proteins p21(ras) metabolism - Transcription Factors genetics - Transcription Factors metabolism - Mutation - CDX2 Transcription Factor genetics - CDX2 Transcription Factor metabolism - Adenocarcinoma genetics - Colorectal Neoplasms pathology - Protein Deficiency - Matrix Attachment Region Binding Proteins genetics - Matrix Attachment Region Binding Proteins metabolism - Brain Neoplasms - Neoplastic Syndromes, Hereditary

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B. subtilis Sec and Srp Systems Show Dynamic Adaptations to Different Conditions of Protein Secretion.
Fiedler SM;Graumann PL
Academic Journal Academic Journal | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE Please log in to see more details
SecA is a widely conserved ATPase that drives the secretion of proteins across the cel... more
B. subtilis Sec and Srp Systems Show Dynamic Adaptations to Different Conditions of Protein Secretion.
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
SecA is a widely conserved ATPase that drives the secretion of proteins across the cell membrane via the SecYEG translocon, while the SRP system is a key player in the insertion of membrane proteins via SecYEG. How SecA gains access to substrate proteins in Bacillus subtilis cells and copes with an increase in substrate availability during biotechnologically desired, high-level expression of secreted proteins is poorly understood. Using single molecule tracking, we found that SecA localization closely mimics that of ribosomes, and its molecule dynamics change similarly to those of ribosomes after inhibition of transcription or translation. These data suggest that B. subtilis SecA associates with signal peptides as they are synthesized at the ribosome, similar to the SRP system. In agreement with this, SecA is a largely mobile cytosolic protein; only a subset is statically associated with the cell membrane, i.e., likely with the Sec translocon. SecA dynamics were considerably different during the late exponential, transition, and stationary growth phases, revealing that single molecule dynamics considerably alter during different genetic programs in cells. During overproduction of a secretory protein, AmyE, SecA showed the strongest changes during the transition phase, i.e., where general protein secretion is high. To investigate whether the overproduction of AmyE also has an influence on other proteins that interact with SecYEG, we analyzed the dynamics of SecDF, YidC, and FtsY with and without AmyE overproduction. SecDF and YidC did not reveal considerable differences in single molecule dynamics during overexpression, while the SRP component FtsY changed markedly in its behavior and became more statically engaged. These findings indicate that the SRP pathway becomes involved in protein secretion upon an overload of proteins carrying a signal sequence. Thus, our data reveal high plasticity of the SecA and SRP systems in dealing with different needs for protein secretion.

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Bacillus subtilis metabolism - Bacterial Proteins metabolism - Membrane Proteins metabolism - SEC Translocation Channels metabolism - Membrane Transport Proteins metabolism - Escherichia coli Proteins genetics

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A zebrafish NLRX1 isoform downregulates fish IFN responses by targeting the adaptor STING.
Zhao X;An L-L;Gong X-Y;Dan C;Qu Z-L;Sun H-Y;Guo W-H;Gui J-F;Zhang Y-B
Academic Journal Academic Journal | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE Please log in to see more details
In mammals, NLRX1 is a unique member of the nucleotide-binding domain and leucine-rich... more
A zebrafish NLRX1 isoform downregulates fish IFN responses by targeting the adaptor STING.
Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE
In mammals, NLRX1 is a unique member of the nucleotide-binding domain and leucine-rich repeat (NLR) family showing an ability to negatively regulate IFN antiviral immunity. Intron-containing genes, including NLRX1, have more than one transcript due to alternative splicing; however, little is known about the function of its splicing variants. Here, we identified a transcript variant of NLRX1 in zebrafish (Danio rerio), termed NLRX1-tv4, as a negative regulator of fish IFN response. Zebrafish NLRX1-tv4 was slightly induced by viral infection, with an expression pattern similar to the full-length NLRX1. Despite the lack of an N-terminal domain that exists in the full-length NLRX1, overexpression of NLRX1-tv4 still impaired fish IFN antiviral response and promoted viral replication in fish cells, similar to the full-length NLRX1. Mechanistically, NLRX1-tv4 targeted STING for proteasome-dependent protein degradation by recruiting an E3 ubiquitin ligase RNF5 to drive the K48-linked ubiquitination, eventually downregulating the IFN antiviral response. Mapping of NLRX1-tv4 domains showed that its N-terminal and C-terminal regions exhibited a similar potential to inhibit STING-mediated IFN antiviral response. Our findings reveal that like the full-length NLRX1, zebrafish NLRX-tv4 functions as an inhibitor to shape fish IFN antiviral response.IMPORTANCEIn this study, we demonstrate that a transcript variant of zebrafish NLRX1, termed NLRX1-tv4, downregulates fish IFN response and promotes virus replication by targeting STING for protein degradation and impairing the interaction of STING and TBK1 and that its N- and C-terminus exhibit a similar inhibitory potential. Our results are helpful in clarifying the current contradictory understanding of structure and function of vertebrate NLRX1s.
Competing Interests: The authors declare no conflict of interest.

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Animals - Immunity, Innate - Protein Domains - Protein Isoforms genetics - Ubiquitin-Protein Ligases - Ubiquitination - Zebrafish immunology - Zebrafish metabolism - Interferons metabolism - Mitochondrial Proteins metabolism - Zebrafish Proteins metabolism - Membrane Proteins metabolism

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Tau-S214 Phosphorylation Inhibits Fyn Kinase Interaction and Increases the Decay Time of NMDAR-mediated Current.
Jos S;Poulose R;Kambaru A;Gogoi H;Dalavaikodihalli Nanjaiah N;Padmanabhan B...
Academic Journal Academic Journal | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 2985088R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1089-8638 (Electronic) Linking ISSN: 00222836 NLM ISO Abbreviation: J Mol Biol Subsets: MEDLINE Please log in to see more details
Fyn kinase SH3 domain interaction with PXXP motif in the Tau protein is implicated in ... more
Tau-S214 Phosphorylation Inhibits Fyn Kinase Interaction and Increases the Decay Time of NMDAR-mediated Current.
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 2985088R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1089-8638 (Electronic) Linking ISSN: 00222836 NLM ISO Abbreviation: J Mol Biol Subsets: MEDLINE
Fyn kinase SH3 domain interaction with PXXP motif in the Tau protein is implicated in AD pathology and is central to NMDAR function. Among seven PXXP motifs localized in proline-rich domain of Tau protein, tandem 5th and 6th PXXP motifs are critical to Fyn-SH3 domain interaction. Here, we report the crystal structure of Fyn-SH3 -Tau (207-221) peptide consisting of 5th and 6th PXXP motif complex to 1.01 Å resolution. Among five AD-specific phosphorylation sites encompassing the 5th and 6th PXXP motifs, only S214 residue showed interaction with SH3 domain. Biophysical studies showed that Tau (207-221) with S214-phosphorylation (pS214) inhibits its interaction with Fyn-SH3 domain. The individual administration of Tau (207-221) with/without pS214 peptides to a single neuron increased the decay time of evoked NMDA current response. Recordings of spontaneous NMDA EPSCs at +40 mV indicate an increase in frequency and amplitude of events for the Tau (207-221) peptide. Conversely, the Tau (207-221) with pS214 peptide exhibited a noteworthy amplitude increase alongside a prolonged decay time. These outcomes underscore the distinctive modalities of action associated with each peptide in the study. Overall, this study provides insights into how Tau (207-221) with/without pS214 affects the molecular framework of NMDAR signaling, indicating its involvement in Tau-related pathogenesis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)

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N-Methylaspartate chemistry - Peptides chemistry - Phosphorylation - Protein Binding - Humans - Protein Stability - Proto-Oncogene Proteins c-fyn chemistry - Proto-Oncogene Proteins c-fyn genetics - src Homology Domains - tau Proteins chemistry - tau Proteins genetics - Proline-Rich Protein Domains - Receptors, N-Methyl-D-Aspartate chemistry

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Identification of novel tail-anchored membrane proteins integrated by the bacterial twin-arginine translocase.
Gallego-Parrilla JJ;Severi E;Chandra G;Palmer T
Academic Journal Academic Journal | Publisher: Microbiology Society Country of Publication: England NLM ID: 9430468 Publication Model: Print Cited Medium: Internet ISSN: 1465-2080 (Electronic) Linking ISSN: 13500872 NLM ISO Abbreviation: Microbiology (Reading) Subsets: MEDLINE Please log in to see more details
The twin-arginine protein transport (Tat) system exports folded proteins across the cy... more
Identification of novel tail-anchored membrane proteins integrated by the bacterial twin-arginine translocase.
Publisher: Microbiology Society Country of Publication: England NLM ID: 9430468 Publication Model: Print Cited Medium: Internet ISSN: 1465-2080 (Electronic) Linking ISSN: 13500872 NLM ISO Abbreviation: Microbiology (Reading) Subsets: MEDLINE
The twin-arginine protein transport (Tat) system exports folded proteins across the cytoplasmic membranes of prokaryotes and the energy transducing-membranes of plant thylakoids and mitochondria. Proteins are targeted to the Tat machinery by N-terminal signal peptides with a conserved twin-arginine motif, and some substrates are exported as heterodimers where the signal peptide is present on one of the partner proteins. A subset of Tat substrates is found in the membrane. Tat-dependent membrane proteins usually have large globular domains and a single transmembrane helix present at the N- or C-terminus. Five Tat substrates that have C-terminal transmembrane helices have previously been characterized in the model bacterium Escherichia coli . Each of these is an iron-sulfur cluster-containing protein involved in electron transfer from hydrogen or formate. Here we have undertaken a bioinformatic search to identify further tail-anchored Tat substrates encoded in bacterial genomes. Our analysis has revealed additional tail-anchored iron-sulfur proteins associated in modules with either a b -type cytochrome or a quinol oxidase. We also identified further candidate tail-anchored Tat substrates, particularly among members of the actinobacterial phylum, that are not predicted to contain cofactors. Using reporter assays, we show experimentally that six of these have both N-terminal Tat signal peptides and C-terminal transmembrane helices. The newly identified proteins include a carboxypeptidase and a predicted protease, and four sortase substrates for which membrane integration is a prerequisite for covalent attachment to the cell wall.

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Membrane Transport Proteins metabolism - Protein Transport - Arginine metabolism - Carrier Proteins metabolism - Protein Sorting Signals - Escherichia coli genetics - Escherichia coli metabolism - Bacterial Proteins genetics - Bacterial Proteins metabolism - Membrane Proteins genetics - Membrane Proteins metabolism - Escherichia coli Proteins metabolism

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Tandem repeats of highly bioluminescent NanoLuc are refolded noncanonically by the Hsp70 machinery.
Apostolidou D;Zhang P;Pandya D;Bock K;Liu Q;Yang W;Marszalek PE
Academic Journal Academic Journal | Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE Please log in to see more details
Chaperones are a large family of proteins crucial for maintaining cellular protein hom... more
Tandem repeats of highly bioluminescent NanoLuc are refolded noncanonically by the Hsp70 machinery.
Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
Chaperones are a large family of proteins crucial for maintaining cellular protein homeostasis. One such chaperone is the 70 kDa heat shock protein (Hsp70), which plays a crucial role in protein (re)folding, stability, functionality, and translocation. While the key events in the Hsp70 chaperone cycle are well established, a relatively small number of distinct substrates were repetitively investigated. This is despite Hsp70 engaging with a plethora of cellular proteins of various structural properties and folding pathways. Here we analyzed novel Hsp70 substrates, based on tandem repeats of NanoLuc (Nluc), a small and highly bioluminescent protein with unique structural characteristics. In previous mechanical unfolding and refolding studies, we have identified interesting misfolding propensities of these Nluc-based tandem repeats. In this study, we further investigate these properties through in vitro bulk experiments. Similar to monomeric Nluc, engineered Nluc dyads and triads proved to be highly bioluminescent. Using the bioluminescence signal as the proxy for their structural integrity, we determined that heat-denatured Nluc dyads and triads can be efficiently refolded by the E. coli Hsp70 chaperone system, which comprises DnaK, DnaJ, and GrpE. In contrast to previous studies with other substrates, we observed that Nluc repeats can be efficiently refolded by DnaK and DnaJ, even in the absence of GrpE co-chaperone. Taken together, our study offers a new powerful substrate for chaperone research and raises intriguing questions about the Hsp70 mechanisms, particularly in the context of structurally diverse proteins.
(© 2024 The Protein Society.)

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Escherichia coli metabolism - Protein Folding - HSP40 Heat-Shock Proteins metabolism - Bacterial Proteins chemistry - HSP70 Heat-Shock Proteins chemistry - Molecular Chaperones chemistry - Heat-Shock Proteins chemistry - Escherichia coli Proteins chemistry - Luciferases

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Methylation of elongation factor 1A by yeast Efm4 or human eEF1A-KMT2 involves a beta-hairpin recognition motif and crosstalks with phosphorylation.
Hamey JJ;Nguyen A;Haddad M;Vázquez-Campos X;Pfeiffer PG;Wilkins MR
Academic Journal Academic Journal | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE Please log in to see more details
Translation elongation factor 1A (eEF1A) is an essential and highly conserved protein ... more
Methylation of elongation factor 1A by yeast Efm4 or human eEF1A-KMT2 involves a beta-hairpin recognition motif and crosstalks with phosphorylation.
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Translation elongation factor 1A (eEF1A) is an essential and highly conserved protein required for protein synthesis in eukaryotes. In both Saccharomyces cerevisiae and human, five different methyltransferases methylate specific residues on eEF1A, making eEF1A the eukaryotic protein targeted by the highest number of dedicated methyltransferases after histone H3. eEF1A methyltransferases are highly selective enzymes, only targeting eEF1A and each targeting just one or two specific residues in eEF1A. However, the mechanism of this selectivity remains poorly understood. To reveal how S. cerevisiae elongation factor methyltransferase 4 (Efm4) specifically methylates eEF1A at K316, we have used AlphaFold-Multimer modeling in combination with crosslinking mass spectrometry (XL-MS) and enzyme mutagenesis. We find that a unique beta-hairpin motif, which extends out from the core methyltransferase fold, is important for the methylation of eEF1A K316 in vitro. An alanine mutation of a single residue on this beta-hairpin, F212, significantly reduces Efm4 activity in vitro and in yeast cells. We show that the equivalent residue in human eEF1A-KMT2 (METTL10), F220, is also important for its activity towards eEF1A in vitro. We further show that the eEF1A guanine nucleotide exchange factor, eEF1Bα, inhibits Efm4 methylation of eEF1A in vitro, likely due to competitive binding. Lastly, we find that phosphorylation of eEF1A at S314 negatively crosstalks with Efm4-mediated methylation of K316. Our findings demonstrate how protein methyltransferases can be highly selective towards a single residue on a single protein in the cell.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Subject terms:

Humans - Methylation - Methyltransferases metabolism - Peptide Elongation Factor 1 genetics - Peptide Elongation Factor 1 chemistry - Peptide Elongation Factor 1 metabolism - Phosphorylation - Models, Molecular - Protein Structure, Tertiary - Protein Structure, Quaternary - Saccharomyces cerevisiae chemistry - Saccharomyces cerevisiae genetics - Saccharomyces cerevisiae metabolism - Saccharomyces cerevisiae Proteins chemistry - Saccharomyces cerevisiae Proteins genetics - Saccharomyces cerevisiae Proteins metabolism

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Escherichia coli strains with precise domain deletions in the ribonuclease RNase E can achieve greatly enhanced levels of membrane protein production.
Vasilopoulou E;Chroumpi T;Skretas G
Academic Journal Academic Journal | Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE Please log in to see more details
Escherichia coli is one of the most widely utilized hosts for production of recombinan... more
Escherichia coli strains with precise domain deletions in the ribonuclease RNase E can achieve greatly enhanced levels of membrane protein production.
Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
Escherichia coli is one of the most widely utilized hosts for production of recombinant membrane proteins (MPs). Bacterial MP production, however, is usually accompanied by severe toxicity and low-level volumetric accumulation. In previous work, we had discovered that co-expression of RraA, an inhibitor of the RNA-degrading activity of RNase E, can efficiently suppress the cytotoxicity associated with the MP overexpression process and, simultaneously, enhance significantly the cellular accumulation of membrane-incorporated recombinant MPs in bacteria. Based on this, we constructed the specialized MP-producing E. coli strain SuptoxR, which can achieve dramatically enhanced volumetric yields of well-folded recombinant MPs. Ιn the present work, we have investigated whether domain deletions in the E. coli RNase E, which exhibit reduced ribonucleolytic activity, can result in suppressed MP-induced toxicity and enhanced recombinant MP production, in a manner resembling the conditions of rraA overexpression in E. coli SuptoxR. We have found that some strains encoding specific RNase E truncation variants can achieve significantly enhanced levels of recombinant MP production. Among these, we have found a single RNase E variant strain, which can efficiently suppress MP-induced toxicity and achieve greatly enhanced levels of recombinant MP production for proteins of both prokaryotic and eukaryotic origin. Based on its properties, and in analogy to the original SuptoxR strain, we have termed this strain SuptoxRNE22. E. coli SuptoxRNE22 can perform better than commercially available bacterial strains, which are frequently utilized for recombinant MP production. We anticipate that SuptoxRNE22 will become a widely utilized host for recombinant MP production in bacteria.
(© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Subject terms:

Ribonucleases genetics - Ribonucleases metabolism - Membrane Proteins metabolism - Endoribonucleases genetics - Endoribonucleases metabolism - Ribonuclease, Pancreatic metabolism - Recombinant Proteins genetics - Recombinant Proteins metabolism - Escherichia coli genetics - Escherichia coli metabolism - Escherichia coli Proteins genetics - Escherichia coli Proteins metabolism

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WAV E3 ubiquitin ligases mediate degradation of IAA32/34 in the TMK1-mediated auxin signaling pathway during apical hook development.
Wang JL;Wang M;Zhang L;Li YX;Li JJ;Li YY;Pu ZX;Li DY;Liu XN;Guo W;Di DW;Li ...
Academic Journal Academic Journal | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE Please log in to see more details
Auxin regulates plant growth and development through downstream signaling pathways, in... more
WAV E3 ubiquitin ligases mediate degradation of IAA32/34 in the TMK1-mediated auxin signaling pathway during apical hook development.
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Auxin regulates plant growth and development through downstream signaling pathways, including the best-known SCF TIR1/AFB -Aux/IAA-ARF pathway and several other less characterized "noncanonical" pathways. Recently, one SCF TIR1/AFB -independent noncanonical pathway, mediated by Transmembrane Kinase 1 (TMK1), was discovered through the analyses of its functions in Arabidopsis apical hook development. Asymmetric accumulation of auxin on the concave side of the apical hook triggers DAR1-catalyzed release of the C-terminal of TMK1, which migrates into the nucleus, where it phosphorylates and stabilizes IAA32/34 to inhibit cell elongation, which is essential for full apical hook formation. However, the molecular factors mediating IAA32/34 degradation have not been identified. Here, we show that proteins in the CYTOKININ INDUCED ROOT WAVING 1 (CKRW1)/WAVY GROWTH 3 (WAV3) subfamily act as E3 ubiquitin ligases to target IAA32/34 for ubiquitination and degradation, which is inhibited by TMK1c-mediated phosphorylation. This antagonistic interaction between TMK1c and CKRW1/WAV3 subfamily E3 ubiquitin ligases regulates IAA32/34 levels to control differential cell elongation along opposite sides of the apical hook.
Competing Interests: Competing interests statement:The authors declare no competing interest.

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Ubiquitin-Protein Ligases genetics - Ubiquitin-Protein Ligases metabolism - Indoleacetic Acids metabolism - Signal Transduction - Ubiquitins metabolism - Gene Expression Regulation, Plant - Arabidopsis Proteins genetics - Arabidopsis Proteins metabolism - Arabidopsis metabolism - F-Box Proteins genetics - F-Box Proteins metabolism

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Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif.
Gaussmann S;Peschel R;Ott J;Zak KM;Sastre J;Delhommel F;Popowicz GM;Boekhov...
Academic Journal Academic Journal | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE Please log in to see more details
Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. By combining bio... more
Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif.
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. By combining biochemical methods and structural biology, we show that the C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif. The SH3 domain also binds WxxxF peptide motifs in the import receptor PEX5, demonstrating evolutionary conservation of such interactions from yeast to human. Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain. Crystal structures reveal how FxxxF and WxxxF/Y motifs are recognized by a non-canonical surface on the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. Surprisingly, the potential PxxP binding surface of the SH3 domain does not recognize PEX14 PxxP motifs, distinct from its yeast ortholog. Our data show that the dynamic network of PEX13 interactions with PEX5 and PEX14, mediated by diaromatic peptide motifs, modulates peroxisomal matrix import.
(© 2024. The Author(s).)

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Humans - Saccharomyces cerevisiae metabolism - Protein Transport physiology - src Homology Domains - Peroxisome-Targeting Signal 1 Receptor metabolism - Peroxisomes metabolism - Peptides chemistry - Protein Binding - Membrane Proteins metabolism - Saccharomyces cerevisiae Proteins metabolism

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Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.
Padmanaban S;Lambacher NJ;Tesmer VM;Zhang J;Shibuya H;Nandakumar J
Academic Journal Academic Journal | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE Please log in to see more details
Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is f... more
Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is fundamental to eukaryotic viability. The protein complex shelterin prevents a DNA damage response at mammalian telomeres. Mammalian shelterin proteins TRF1 and TRF2 and their homologs in yeast and protozoa protect telomeric dsDNA. N-terminal homodimerization and C-terminal Myb-domain-mediated dsDNA binding are two structural hallmarks of end protection by TRF homologs. Yet our understanding of how Caenorhabditis elegans protects its telomeric dsDNA is limited. Recently identified C. elegans proteins TEBP-1 (also called DTN-1) and TEBP-2 (also called DTN-2) are functional homologs of TRF proteins, but how they bind DNA and whether or how they dimerize is not known. TEBP-1 and TEBP-2 harbor three Myb-containing domains (MCDs) and no obvious dimerization domain. We demonstrate biochemically that only the third MCD binds DNA. We solve the X-ray crystal structure of TEBP-2 MCD3 with telomeric dsDNA to reveal the structural mechanism of telomeric dsDNA protection in C. elegans . Mutagenesis of the DNA-binding site of TEBP-1 and TEBP-2 compromises DNA binding in vitro, and increases DNA damage signaling, lengthens telomeres, and decreases brood size in vivo. Via an X-ray crystal structure, biochemical validation of the dimerization interface, and SEC-MALS analysis, we demonstrate that MCD1 and MCD2 form a composite dimerization module that facilitates not only TEBP-1 and TEBP-2 homodimerization but also heterodimerization. These findings provide fundamental insights into C. elegans telomeric dsDNA protection and highlight how different eukaryotes have evolved distinct strategies to solve the chromosome end protection problem.
Competing Interests: Competing interests statement:The authors declare no competing interest.

Subject terms:

Animals - Caenorhabditis elegans genetics - Caenorhabditis elegans metabolism - Dimerization - Telomeric Repeat Binding Protein 1 genetics - Telomeric Repeat Binding Protein 1 chemistry - Telomeric Repeat Binding Protein 1 metabolism - Protein Binding - Telomere genetics - Telomere metabolism - Shelterin Complex - DNA metabolism - Telomeric Repeat Binding Protein 2 - Mammals genetics - Telomere-Binding Proteins metabolism - Caenorhabditis elegans Proteins genetics - Caenorhabditis elegans Proteins metabolism

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