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Structure of the human L-type voltage-gated calcium channel Cav1.2 complexed with L-leucineStructure of the human L-type voltage-gated calcium channel Cav1.2 complexed with L-leucine
Structural highlights
FunctionCA2D1_RABIT The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling. Publication Abstract from PubMedVoltage-gated ion channels (VGICs) comprise multiple structural units whose assembly is required for function(1,2). There is scant structural understanding of how VGIC subunits assemble and whether chaperone proteins are required. High-voltage activated calcium channels (Ca(V)s)(3,4) are paradigmatic multi-subunit VGICs whose function and trafficking is powerfully shaped by interactions between pore-forming Ca(V)1 or Ca(V)2 Ca(V)alpha(1)(3) and auxiliary Ca(V)beta(5), and Ca(V)alpha(2)delta subunits(6,7). Here, we present cryo-EM structures of human brain and cardiac Ca(V)1.2 bound with Ca(V)beta(3) to a chaperone, the endoplasmic reticulum membrane protein complex (EMC)(8,9), and of the assembled Ca(V)1.2/Ca(V)beta(3)/Ca(V)alpha(2)delta-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 Ca(V)alpha(2)delta interaction site. The structures identify the Ca(V)alpha(2)delta binding site for gabapentinoid anti-pain and anti-anxiety drugs(6), show that EMC and Ca(V)alpha(2)delta channel interactions are mutually exclusive, and indicate that EMC to Ca(V)alpha(2)delta handoff involves a divalent ion-dependent step and Ca(V)1.2 element ordering. Disruption of the EMC:Ca(V) complex compromises Ca(V) function suggesting that the EMC acts as a channel holdase that facilitates channel assembly. Together, the structures unveil a Ca(V) assembly intermediate and EMC client binding sites, with potentially wide-reading implications for biogenesis of VGICs and other membrane proteins. EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.,Chen Z, Mondal A, Ali FA, Jang S, Niranjan S, Montano JL, Zaro BW, Minor DL Jr Nature. 2023 May 17. doi: 10.1038/s41586-023-06175-5. PMID:37196677[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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