EMC holdase:CaV1.2/CaVβ3 complex and CaV1.2 channel structures reveal CaV assembly and drug binding mechanisms

Voltage-gated ion channels (VGICs) comprise multiple structural units whose assembly is required for function[1][1],[2][2]. There is scant structural understanding of how VGIC subunits assemble and whether chaperone proteins are required. High-voltage activated calcium channels (CaVs)[3][3],[4][4] are paradigmatic multi-subunit VGICs from electrically excitable tissues whose function and trafficking is powerfully shaped by interactions between pore-forming CaV1 or CaV2 CaVα13 and auxiliary CaVβ5, and CaVα2δ subunits[6][5],[7][6]. 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][7],[9][8], and of the isolated CaV1.2/CaVβ3/CaVα2δ-1 channel. These provide an unprecedented view of an EMC holdase:client complex and define EMC sites, the TM and Cyto docks, whose interaction with the client channel cause partial extraction of a pore subunit and splay open the CaVα2δ interaction site. The structures further identify the CaVα2δ binding site for gabapentinoid anti-pain and anti-anxiety drugs[6][5], show that EMC and CaVα2δ channel interactions are mutually exclusive, and indicate that EMC to CaVα2δ handoff involves a Ca2+-dependent step and ordering of multiple CaV1.2 elements. Together, the structures unveil a CaV assembly intermediate and previously unknown EMC client binding sites that have broad implications for biogenesis of VGICs and other membrane proteins. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-6 [6]: #ref-7 [7]: #ref-8 [8]: #ref-9