8EOG

Structure of the human L-type voltage-gated calcium channel Cav1.2 complexed with L-leucine

Summary for 8EOG

• Entry DOI: 10.2210/pdb8eog/pdb
• EMDB information: 28375 28561 28564
• Descriptor: Voltage-dependent calcium channel subunit alpha-2/delta-1, CHOLESTEROL, (2R)-3-{[(R)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-2-(dodecanoyloxy)propyl dodecanoate, ... (13 entities in total)
• Functional Keywords: voltage-gated calcium channel, cav alpha2delta, drug binding, gabapentinoid, membrane protein
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 3
• Total formula weight: 316630.21

Authors

Chen, Z.,Mondal, A.,Abderemane-Ali, F.,Minor, D.L. (deposition date: 2022-10-03, release date: 2023-05-24, Last modification date: 2024-10-23)

Primary citation

Chen, Z.,Mondal, A.,Abderemane-Ali, F.,Jang, S.,Niranjan, S.,Montano, J.L.,Zaro, B.W.,Minor Jr., D.L.
EMC chaperone-Ca V structure reveals an ion channel assembly intermediate.
Nature, 619:410-419, 2023

PubMed Abstract: Voltage-gated ion channels (VGICs) comprise multiple structural units, the assembly of which is required for function. Structural understanding of how VGIC subunits assemble and whether chaperone proteins are required is lacking. High-voltage-activated calcium channels (Cas) are paradigmatic multisubunit VGICs whose function and trafficking are powerfully shaped by interactions between pore-forming Ca1 or Ca2 Caα (ref. ), and the auxiliary Caβ and Caαδ subunits. Here we present cryo-electron microscopy structures of human brain and cardiac Ca1.2 bound with Caβ to a chaperone-the endoplasmic reticulum membrane protein complex (EMC)-and of the assembled Ca1.2-Caβ-Caαδ-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 Caαδ-interaction site. The structures identify the Caαδ-binding site for gabapentinoid anti-pain and anti-anxiety drugs, show that EMC and Caαδ interactions with the channel are mutually exclusive, and indicate that EMC-to-Caαδ hand-off involves a divalent ion-dependent step and Ca1.2 element ordering. Disruption of the EMC-Ca complex compromises Ca function, suggesting that the EMC functions as a channel holdase that facilitates channel assembly. Together, the structures reveal a Ca assembly intermediate and EMC client-binding sites that could have wide-ranging implications for the biogenesis of VGICs and other membrane proteins.

PubMed: 37196677
DOI: 10.1038/s41586-023-06175-5

Experimental method

ELECTRON MICROSCOPY (3.3 Å)