Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia.

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. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and 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. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with Gβγ and show reduced condi

SUBMITTER: Yen YC 

PROVIDER: S-EPMC11329361 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature