Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ

The nine different membrane-anchored adenylyl cyclase isoforms (AC1–9) in mammals are stimulated by the heterotrimeric G protein Gα(s), but their response to Gβγ regulation is isoform-specific. For example, AC5 is conditionally activated by Gβγ. Here, we report cryo-EM structures of ligand-free AC5...

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Autores principales: Yen, Yu-Chen, Li, Yong, Chen, Chun-Liang, Klose, Thomas, Watts, Val J, Dessauer, Carmen W, Tesmer, John J. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187219/
https://www.ncbi.nlm.nih.gov/pubmed/37205557
http://dx.doi.org/10.1101/2023.05.02.539090
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author Yen, Yu-Chen
Li, Yong
Chen, Chun-Liang
Klose, Thomas
Watts, Val J
Dessauer, Carmen W
Tesmer, John J. G.
author_facet Yen, Yu-Chen
Li, Yong
Chen, Chun-Liang
Klose, Thomas
Watts, Val J
Dessauer, Carmen W
Tesmer, John J. G.
author_sort Yen, Yu-Chen
collection PubMed
description The nine different membrane-anchored adenylyl cyclase isoforms (AC1–9) in mammals are stimulated by the heterotrimeric G protein Gα(s), but their response to Gβγ regulation is isoform-specific. For example, AC5 is conditionally activated by Gβγ. Here, we report cryo-EM structures of ligand-free AC5 in complex with Gβγ and of a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C(1b)) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. The interface with Gβγ involves AC5 residues that are subject to gain-of-function mutations in humans with familial dyskinesia, indicating that the observed interaction is important for motor function. A molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core, is proposed. Because our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.
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spelling pubmed-101872192023-05-17 Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ Yen, Yu-Chen Li, Yong Chen, Chun-Liang Klose, Thomas Watts, Val J Dessauer, Carmen W Tesmer, John J. G. bioRxiv Article The nine different membrane-anchored adenylyl cyclase isoforms (AC1–9) in mammals are stimulated by the heterotrimeric G protein Gα(s), but their response to Gβγ regulation is isoform-specific. For example, AC5 is conditionally activated by Gβγ. Here, we report cryo-EM structures of ligand-free AC5 in complex with Gβγ and of a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C(1b)) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. The interface with Gβγ involves AC5 residues that are subject to gain-of-function mutations in humans with familial dyskinesia, indicating that the observed interaction is important for motor function. A molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core, is proposed. Because our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development. Cold Spring Harbor Laboratory 2023-05-02 /pmc/articles/PMC10187219/ /pubmed/37205557 http://dx.doi.org/10.1101/2023.05.02.539090 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Yen, Yu-Chen
Li, Yong
Chen, Chun-Liang
Klose, Thomas
Watts, Val J
Dessauer, Carmen W
Tesmer, John J. G.
Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
title Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
title_full Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
title_fullStr Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
title_full_unstemmed Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
title_short Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
title_sort isoform specific regulation of adenylyl cyclase 5 by gβγ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187219/
https://www.ncbi.nlm.nih.gov/pubmed/37205557
http://dx.doi.org/10.1101/2023.05.02.539090
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