Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ.

ABSTRACT: 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 dyskin

SUBMITTER: Yen YC 

PROVIDER: S-EPMC10187219 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature