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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1785042705089298432 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10187219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yenyuchen isoformspecificregulationofadenylylcyclase5bygbg AT liyong isoformspecificregulationofadenylylcyclase5bygbg AT chenchunliang isoformspecificregulationofadenylylcyclase5bygbg AT klosethomas isoformspecificregulationofadenylylcyclase5bygbg AT wattsvalj isoformspecificregulationofadenylylcyclase5bygbg AT dessauercarmenw isoformspecificregulationofadenylylcyclase5bygbg AT tesmerjohnjg isoformspecificregulationofadenylylcyclase5bygbg |