8sl4

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Dimeric form of human adenylyl cyclase 5

Structural highlights

8sl4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 7Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ADCY5_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.

Function

ADCY5_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 PubMed

The 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.

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References

  1. ↑ Ding Q, Gros R, Gray ID, Taussig R, Ferguson SS, Feldman RD. Raf kinase activation of adenylyl cyclases: isoform-selective regulation. Mol Pharmacol. 2004 Oct;66(4):921-8. PMID:15385642 doi:10.1124/mol.66.4.
  2. ↑ Chen YZ, Friedman JR, Chen DH, Chan GC, Bloss CS, Hisama FM, Topol SE, Carson AR, Pham PH, Bonkowski ES, Scott ER, Lee JK, Zhang G, Oliveira G, Xu J, Scott-Van Zeeland AA, Chen Q, Levy S, Topol EJ, Storm D, Swanson PD, Bird TD, Schork NJ, Raskind WH, Torkamani A. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol. 2014 Apr;75(4):542-9. PMID:24700542 doi:10.1002/ana.24119
  3. ↑ Hodson DJ, Mitchell RK, Marselli L, Pullen TJ, Gimeno Brias S, Semplici F, Everett KL, Cooper DM, Bugliani M, Marchetti P, Lavallard V, Bosco D, Piemonti L, Johnson PR, Hughes SJ, Li D, Li WH, Shapiro AM, Rutter GA. ADCY5 couples glucose to insulin secretion in human islets. Diabetes. 2014 Sep;63(9):3009-21. PMID:24740569 doi:10.2337/db13-1607
  4. ↑ Brand CS, Sadana R, Malik S, Smrcka AV, Dessauer CW. Adenylyl Cyclase 5 Regulation by Gbetagamma Involves Isoform-Specific Use of Multiple Interaction Sites. Mol Pharmacol. 2015 Oct;88(4):758-67. doi: 10.1124/mol.115.099556. Epub 2015 Jul , 23. PMID:26206488 doi:http://dx.doi.org/10.1124/mol.115.099556
  5. ↑ Yen YC, Li Y, Chen CL, Klose T, Watts VJ, Dessauer CW, Tesmer JJG. Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia. Nat Struct Mol Biol. 2024 Aug;31(8):1189-1197. PMID:38589608 doi:10.1038/s41594-024-01263-0

Contents


PDB ID 8sl4

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