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Stabilization of interdomain interactions in G protein α subunits as a determinant of Gα i subtype signaling specificity.

التفاصيل البيبلوغرافية
العنوان: Stabilization of interdomain interactions in G protein α subunits as a determinant of Gα i subtype signaling specificity.
المؤلفون: Lefevre TJ; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, USA., Wei W; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA., Mukhaleva E; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA., Meda Venkata SP; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Chandan NR; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Genentech, South San Francisco, California, USA., Abraham S; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Li Y; Department of Integrative Biology and Pharmacology McGovern Medical School, UTHealth, Houston, Texas, USA., Dessauer CW; Department of Integrative Biology and Pharmacology McGovern Medical School, UTHealth, Houston, Texas, USA., Vaidehi N; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA., Smrcka AV; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address: avsmrcka@umich.edu.
المصدر: The Journal of biological chemistry [J Biol Chem] 2024 May; Vol. 300 (5), pp. 107211. Date of Electronic Publication: 2024 Mar 22.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: 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
أسماء مطبوعة: Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
مواضيع طبية MeSH: GTP-Binding Protein alpha Subunits, Gi-Go*/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go*/chemistry , GTP-Binding Protein alpha Subunits, Gi-Go*/genetics , Signal Transduction*, Humans ; Molecular Dynamics Simulation ; GTP-Binding Protein alpha Subunit, Gi2/metabolism ; GTP-Binding Protein alpha Subunit, Gi2/genetics ; GTP-Binding Protein alpha Subunit, Gi2/chemistry ; HEK293 Cells ; Protein Domains ; Protein Stability ; Protein Binding
مستخلص: Highly homologous members of the Gα i family, Gα i1-3 , have distinct tissue distributions and physiological functions, yet their biochemical and functional properties are very similar. We recently identified PDZ-RhoGEF (PRG) as a novel Gα i1 effector that is poorly activated by Gα i2 . In a proteomic proximity labeling screen we observed a strong preference for Gα i1 relative to Gα i2 with respect to engagement of a broad range of potential targets. We investigated the mechanistic basis for this selectivity using PRG as a representative target. Substitution of either the helical domain (HD) from Gα i1 into Gα i2 or substitution of a single amino acid, A230 in Gα i2 with the corresponding D in Gα i1 , largely rescues PRG activation and interactions with other potential Gα i targets. Molecular dynamics simulations combined with Bayesian network models revealed that in the GTP bound state, separation at the HD-Ras-like domain (RLD) interface is more pronounced in Gα i2 than Gα i1 . Mutation of A230 to D in Gα i2 stabilizes HD-RLD interactions via ionic interactions with R145 in the HD which in turn modify the conformation of Switch III. These data support a model where D229 in Gα i1 interacts with R144 and stabilizes a network of interactions between HD and RLD to promote protein target recognition. The corresponding A230 in Gα i2 is unable to stabilize this network leading to an overall lower efficacy with respect to target interactions. This study reveals distinct mechanistic properties that could underly differential biological and physiological consequences of activation of Gα i1 or Gα i2 by G protein-coupled receptors.
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.)
التعليقات: Update of: bioRxiv. 2023 Apr 06:2023.03.10.532072. doi: 10.1101/2023.03.10.532072. (PMID: 37066214)
معلومات مُعتمدة: R35 GM127303 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: G protein–coupled receptor; Rho GEF; alpha subunits; domain interactions; effector coupling; heterotrimeric G protein; mass spectrometry; proximity labeling; structure
المشرفين على المادة: EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
EC 3.6.5.1 (GTP-Binding Protein alpha Subunit, Gi2)
تواريخ الأحداث: Date Created: 20240324 Date Completed: 20240529 Latest Revision: 20240611
رمز التحديث: 20240612
مُعرف محوري في PubMed: PMC11066577
DOI: 10.1016/j.jbc.2024.107211
PMID: 38522511
قاعدة البيانات: MEDLINE
الوصف
تدمد:1083-351X
DOI:10.1016/j.jbc.2024.107211