EMC chaperone

Nature (2023)Cite this article

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Voltage-gated ion channels (VGICs) comprise multiple structural units whose assembly is required for function1,2. There is scant structural understanding of how VGIC subunits assemble and whether chaperone proteins are required. High-voltage activated calcium channels (CaVs)3,4 are paradigmatic multi-subunit VGICs whose function and trafficking is powerfully shaped by interactions between pore-forming CaV1 or CaV2 CaVα13 and auxiliary CaVβ5, and CaVα2δ subunits6,7. Here, we present cryo-EM structures of human brain and cardiac CaV1.2 bound with CaVβ3 to a chaperone, the endoplasmic reticulum membrane protein complex (EMC)8,9, and of the assembled CaV1.2/CaVβ3/CaVα2δ-1 channel. These provide a view of an EMC:client complex and define EMC sites, the TM and Cyto docks, whose interaction with the client channel causes partial extraction of a pore subunit and splays open the CaVα2δ interaction site. The structures identify the CaVα2δ binding site for gabapentinoid anti-pain and anti-anxiety drugs6, show that EMC and CaVα2δ channel interactions are mutually exclusive, and indicate that EMC to CaVα2δ handoff involves a divalent ion-dependent step and CaV1.2 element ordering. Disruption of the EMC:CaV complex compromises CaV function suggesting that the EMC acts as a channel holdase that facilitates channel assembly. Together, the structures unveil a CaV assembly intermediate and EMC client binding sites, with potentially wide-reading implications for biogenesis of VGICs and other membrane proteins.

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Fayal Abderemane Ali

Present address: Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Cardiovascular Research Institute, University of California, San Francisco, California, USA

Zhou Chen, Abhisek Mondal, Fayal Abderemane Ali, Seil Jang, Sangeeta Niranjan, Balyn W. Zaro & Daniel L. Minor Jr.

Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA

José L. Montaño & Balyn W. Zaro

Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA

Daniel L. Minor Jr.

California Institute for Quantitative Biomedical Research, University of California, San Francisco, California, USA

Daniel L. Minor Jr.

Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California, USA

Daniel L. Minor Jr.

Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA

Daniel L. Minor Jr.

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Correspondence to Daniel L. Minor Jr..

This file contains Supplementary Figures 1-9, full legends for Supplementary Videos 1-12, Supplementary Table 2 and Supplementary References.

Proteins identified by mass spectrometry. Data for: a, CaV1.2(ΔC)/CaVβ3, CaV1.2(ΔC) alone, and CaVβ3 alone, b, CaV1.2/CaVβ3, and c, CaV1.2(ΔC)/CaVβ3(11A). Filters were applied as described in experimental methods. (See separate Excel spreadsheets).

Overview of the EMC:CaV1.2/CaVβ3 complex – see Supplementary Information document for details.

Lumenal view of CaV1.2 conformational changes upon EMC binding – see Supplementary Information document for details.

Side view of CaV1.2 conformational changes upon EMC binding – see Supplementary Information document for details.

CaV1.2 VSD I conformational changes upon EMC binding – see Supplementary Information document for details.

CaV1.2 VSD II conformational changes upon EMC binding – see Supplementary Information document for details.

CaV1.2 VSD IV conformational changes upon EMC binding – see Supplementary Information document for details.

CaV1.2 PD III conformational changes upon EMC binding – see Supplementary Information document for details.

CaV1.2 PD II conformational changes upon EMC binding – see Supplementary Information document for details.

CaV1.2 PD IV conformational changes upon EMC binding – see Supplementary Information document for details.

EMC lumenal domain movement induced by client binding – see Supplementary Information document for details.

EMC transmembrane domain movement induced by client binding – see Supplementary Information document for details.

Reprints and Permissions

Chen, Z., Mondal, A., Ali, F.A. et al. EMC chaperone-CaV structure reveals an ion channel assembly intermediate. Nature (2023). https://doi.org/10.1038/s41586-023-06175-5

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Received: 03 October 2022

Accepted: 05 May 2023

Published: 17 May 2023

DOI: https://doi.org/10.1038/s41586-023-06175-5

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