Structural basis of adenylyl cyclase 9 activation

Chao Qi, Pia Lavriha, Ved Mehta, Basavraj Khanppnavar, Inayathulla Mohammed, Yong Li, Michalis Lazaratos, Jonas V. Schaefer, Birgit Dreier, Andreas Plückthun, Ana-Nicoleta Bondar, Carmen W. Dessauer and Volodymyr M. Korkhov ()
Additional contact information
Chao Qi: Institute of Molecular Biology and Biophysics, ETH
Pia Lavriha: Paul Scherrer Institute
Ved Mehta: Institute of Molecular Biology and Biophysics, ETH
Basavraj Khanppnavar: Institute of Molecular Biology and Biophysics, ETH
Inayathulla Mohammed: Biozentrum, University of Basel
Yong Li: University of Texas Health Science Center
Michalis Lazaratos: Freie Universität Berlin
Jonas V. Schaefer: University of Zurich
Birgit Dreier: University of Zurich
Andreas Plückthun: University of Zurich
Ana-Nicoleta Bondar: Freie Universität Berlin
Carmen W. Dessauer: University of Texas Health Science Center
Volodymyr M. Korkhov: Institute of Molecular Biology and Biophysics, ETH

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus. Although our recent structural studies of the AC9-Gαs complex provided the framework for understanding AC9 autoinhibition, the conformational changes that AC9 undergoes in response to activator binding remains poorly understood. Here, we present the cryo-EM structures of AC9 in several distinct states: (i) AC9 bound to a nucleotide inhibitor MANT-GTP, (ii) bound to an artificial activator (DARPin C4) and MANT-GTP, (iii) bound to DARPin C4 and a nucleotide analogue ATPαS, (iv) bound to Gαs and MANT-GTP. The artificial activator DARPin C4 partially activates AC9 by binding at a site that overlaps with the Gαs binding site. Together with the previously observed occluded and forskolin-bound conformations, structural comparisons of AC9 in the four conformations described here show that secondary structure rearrangements in the region surrounding the forskolin binding site are essential for AC9 activation.

Date: 2022
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28685-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28685-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28685-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().