دورية أكاديمية
أعرض في EDS

Divergent folding-mediated epistasis among unstable membrane protein variants.

التفاصيل البيبلوغرافية
العنوان: Divergent folding-mediated epistasis among unstable membrane protein variants.
المؤلفون: Chamness LM; Department of Chemistry, Indiana University, Bloomington, United States., Kuntz CP; The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, United States., McKee AG; Department of Chemistry, Indiana University, Bloomington, United States., Penn WD; Department of Chemistry, Indiana University, Bloomington, United States., Hemmerich CM; Center for Genomics and Bioinformatics, Indiana University, Bloomington, United States., Rusch DB; Center for Genomics and Bioinformatics, Indiana University, Bloomington, United States., Woods H; Department of Chemistry, Vanderbilt University, Nashville, United States.; Chemical and Physical Biology Program, Vanderbilt University, Nashville, United States., Dyotima; Department of Chemistry, Indiana University, Bloomington, United States., Meiler J; Department of Chemistry, Vanderbilt University, Nashville, United States.; Institute for Drug Discovery, Leipzig University, Leipzig, Germany., Schlebach JP; The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, United States.
المصدر: ELife [Elife] 2024 Jul 30; Vol. 12. Date of Electronic Publication: 2024 Jul 30.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Protein Folding* , Epistasis, Genetic* , Receptors, LHRH*/genetics , Receptors, LHRH*/metabolism , Receptors, LHRH*/chemistry , Membrane Proteins*/genetics , Membrane Proteins*/metabolism , Membrane Proteins*/chemistry, Humans ; Mutation ; Protein Stability ; Cell Membrane/metabolism
مستخلص: Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for the mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear to have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability is known to shape evolution, it is unclear how cotranslational folding constraints modulate the synergistic, epistatic interactions between mutations. We therefore compared the pairwise interactions formed by mutations that disrupt the membrane topology (V276T) or tertiary structure (W107A) of GnRHR. Using deep mutational scanning, we evaluated how the plasma membrane expression of these variants is modified by hundreds of secondary mutations. An analysis of 251 mutants in three genetic backgrounds reveals that V276T and W107A form distinct epistatic interactions that depend on both the severity and the mechanism of destabilization. V276T forms predominantly negative epistatic interactions with destabilizing mutations in soluble loops. In contrast, W107A forms positive interactions with mutations in both loops and transmembrane domains that reflect the diminishing impacts of the destabilizing mutations in variants that are already unstable. These findings reveal how epistasis is remodeled by conformational defects in membrane proteins and in unstable proteins more generally.
Competing Interests: LC, CK, AM, WP, CH, DR, HW, D, JM, JS No competing interests declared
(© 2023, Chamness et al.)
التعليقات: Update of: bioRxiv. 2024 Feb 01:2023.08.25.554866. doi: 10.1101/2023.08.25.554866. (PMID: 37662415)
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معلومات مُعتمدة: R01 GM129261 United States GM NIGMS NIH HHS; R01GM129261 United States NH NIH HHS; 1342962 National Science Foundation
فهرسة مساهمة: Keywords: epistasis; human; membrane protein folding; molecular biophysics; protein evolution; protein misfolding; structural biology; translocon
المشرفين على المادة: 0 (Receptors, LHRH)
0 (Membrane Proteins)
0 (GNRHR protein, human)
تواريخ الأحداث: Date Created: 20240730 Date Completed: 20240730 Latest Revision: 20240801
رمز التحديث: 20240801
مُعرف محوري في PubMed: PMC11288631
DOI: 10.7554/eLife.92406
PMID: 39078397
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.92406