Structure of Mycobacterium tuberculosis Cya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases
- Paul Scherrer Institute, Switzerland
- ETH Zurich, Switzerland
- University of Zurich, Switzerland
Abstract
Mycobacterium tuberculosis adenylyl cyclase (AC) Rv1625c / Cya is an evolutionary ancestor of the mammalian membrane ACs and a model system for studies of their structure and function. Although the vital role of ACs in cellular signaling is well established, the function of their transmembrane (TM) regions remains unknown. Here we describe the cryo-EM structure of Cya bound to a stabilizing nanobody at 3.6 Å resolution. The TM helices 1-5 form a structurally conserved domain that facilitates the assembly of the helical and catalytic domains. The TM region contains discrete pockets accessible from the extracellular and cytosolic side of the membrane. Neutralization of the negatively charged extracellular pocket Ex1 destabilizes the cytosolic helical domain and reduces the catalytic activity of the enzyme. The TM domain acts as a functional component of Cya, guiding the assembly of the catalytic domain and providing the means for direct regulation of catalytic activity in response to extracellular ligands.
Data availability
The atomic coordinates and structure factors have been deposited in the Protein Data Bank (7YZ9, 7YZI, 7YZK); the density maps have been deposited in the Electron Microscopy Data Bank (EMD-14388, EMD-14389). The mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD033826. All other data are available in the main text or the supplementary materials.
Article and author information
Author details
Volodymyr M. Korkhov
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (150665)
- Volodymyr M. Korkhov
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (176992)
- Volodymyr M. Korkhov
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (184951)
- Volodymyr M. Korkhov
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Preprint posted: December 1, 2021 (view preprint)
- Received: January 13, 2022
- Accepted: August 17, 2022
- Accepted Manuscript published: August 18, 2022 (version 1)
- Accepted Manuscript updated: August 22, 2022 (version 2)
- Version of Record published: August 31, 2022 (version 3)
Copyright
© 2022, Mehta et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of Mycobacterium tuberculosis Cya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases
eLife 11:e77032.
https://doi.org/10.7554/eLife.77032
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