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Structural and Functional Implication of Natural Variants of Gαs

Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status...

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Autores principales: Jeong, Yejin, Chung, Ka Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959179/
https://www.ncbi.nlm.nih.gov/pubmed/36835474
http://dx.doi.org/10.3390/ijms24044064
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author Jeong, Yejin
Chung, Ka Young
author_facet Jeong, Yejin
Chung, Ka Young
author_sort Jeong, Yejin
collection PubMed
description Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status of G proteins. Interaction of guanosine diphosphate (GDP) or guanosine triphosphate (GTP) with Gα switches G protein into basal or active states, respectively. Genetic alteration in Gα could be responsible for the development of various diseases due to its critical role in cell signaling. Specifically, loss-of-function mutations of Gαs are associated with parathyroid hormone-resistant syndrome such as inactivating parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) signaling disorders (iPPSDs), whereas gain-of-function mutations of Gαs are associated with McCune–Albright syndrome and tumor development. In the present study, we analyzed the structural and functional implications of natural variants of the Gαs subtype observed in iPPSDs. Although a few tested natural variants did not alter the structure and function of Gαs, others induced drastic conformational changes in Gαs, resulting in improper folding and aggregation of the proteins. Other natural variants induced only mild conformational changes but altered the GDP/GTP exchange kinetics. Therefore, the results shed light on the relationship between natural variants of Gα and iPPSDs.
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spelling pubmed-99591792023-02-26 Structural and Functional Implication of Natural Variants of Gαs Jeong, Yejin Chung, Ka Young Int J Mol Sci Article Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status of G proteins. Interaction of guanosine diphosphate (GDP) or guanosine triphosphate (GTP) with Gα switches G protein into basal or active states, respectively. Genetic alteration in Gα could be responsible for the development of various diseases due to its critical role in cell signaling. Specifically, loss-of-function mutations of Gαs are associated with parathyroid hormone-resistant syndrome such as inactivating parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) signaling disorders (iPPSDs), whereas gain-of-function mutations of Gαs are associated with McCune–Albright syndrome and tumor development. In the present study, we analyzed the structural and functional implications of natural variants of the Gαs subtype observed in iPPSDs. Although a few tested natural variants did not alter the structure and function of Gαs, others induced drastic conformational changes in Gαs, resulting in improper folding and aggregation of the proteins. Other natural variants induced only mild conformational changes but altered the GDP/GTP exchange kinetics. Therefore, the results shed light on the relationship between natural variants of Gα and iPPSDs. MDPI 2023-02-17 /pmc/articles/PMC9959179/ /pubmed/36835474 http://dx.doi.org/10.3390/ijms24044064 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jeong, Yejin
Chung, Ka Young
Structural and Functional Implication of Natural Variants of Gαs
title Structural and Functional Implication of Natural Variants of Gαs
title_full Structural and Functional Implication of Natural Variants of Gαs
title_fullStr Structural and Functional Implication of Natural Variants of Gαs
title_full_unstemmed Structural and Functional Implication of Natural Variants of Gαs
title_short Structural and Functional Implication of Natural Variants of Gαs
title_sort structural and functional implication of natural variants of gαs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959179/
https://www.ncbi.nlm.nih.gov/pubmed/36835474
http://dx.doi.org/10.3390/ijms24044064
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