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TitleStructure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateApr 8, 2024
AuthorsYu-Chen Yen / Yong Li / Chun-Liang Chen / Thomas Klose / Val J Watts / Carmen W Dessauer / John J G Tesmer /
PubMed AbstractThe nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gα, but their response to Gβγ regulation is isoform specific. In ...The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gα, 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) 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 conditional activation by Gβγ, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As 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.
External linksNat Struct Mol Biol / PubMed:38589608
MethodsEM (single particle)
Resolution7.0 Å
Structure data

40572

8sl3

EMDB-40572, PDB-8sl3:
Human adenylyl Cyclase 5 in complex with Gbg
Method: EM (single particle) / Resolution: 7.0 Å

Chemicals

ChemComp-GER:
GERAN-8-YL GERAN

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Adenylyl cyclase / G-proteins / complex

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