8sl3
Human adenylyl Cyclase 5 in complex with Gbg
Structural highlights
DiseaseADCY5_HUMAN Familial dyskinesia and facial myokymia;Benign hereditary chorea. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionADCY5_HUMAN Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:24700542, PubMed:26206488). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569).[1] [2] [3] [4] Publication Abstract from PubMedThe nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Galpha(s), but their response to Gbetagamma regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gbetagamma and a dimeric form of AC5 that could be involved in its regulation. Gbetagamma 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 Gbetagamma 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 Gbetagamma and show reduced conditional activation by Gbetagamma, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gbetagamma 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. Structure of adenylyl cyclase 5 in complex with Gbetagamma offers insights into ADCY5-related dyskinesia.,Yen YC, Li Y, Chen CL, Klose T, Watts VJ, Dessauer CW, Tesmer JJG Nat Struct Mol Biol. 2024 Aug;31(8):1189-1197. doi: 10.1038/s41594-024-01263-0. , Epub 2024 Apr 8. PMID:38589608[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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