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Structure 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, the assembly of which is required for function(1,2). Structural understanding of how VGIC subunits assemble and whether chaperone proteins are required is lacking. High-voltage-activated calcium channels (Ca(V)s)(3,4) are paradigmatic multisubunit VGICs whose function and trafficking are powerfully shaped by interactions between pore-forming Ca(V)1 or Ca(V)2 Ca(V)alpha(1) (ref. (3)), and the auxiliary Ca(V)beta(5) and Ca(V)alpha(2)delta subunits(6,7). Here we present cryo-electron microscopy 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 structures provide a view of an EMC-client complex and define EMC sites-the transmembrane (TM) and cytoplasmic (Cyto) docks; interaction between these sites and 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 interactions with the channel are mutually exclusive, and indicate that EMC-to-Ca(V)alpha(2)delta hand-off 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 functions as a channel holdase that facilitates channel assembly. Together, the structures reveal a Ca(V) assembly intermediate and EMC client-binding sites that could have wide-ranging implications for the biogenesis of VGICs and other membrane proteins. EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.,Chen Z, Mondal A, Abderemane-Ali F, Jang S, Niranjan S, Montano JL, Zaro BW, Minor DL Jr Nature. 2023 Jul;619(7969):410-419. doi: 10.1038/s41586-023-06175-5. Epub 2023 , May 17. PMID:37196677[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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