Structure of human R-type voltage-gated CaV2.3-alpha2/delta1-beta1 channel complex in the ligand-free (apo) state
Structural highlights
7xlq is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
CAC1E_HUMAN The disease is caused by variants affecting the gene represented in this entry.
Function
CAC1E_HUMAN Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells (PubMed:30343943). They are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1E gives rise to R-type calcium currents. R-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by nickel. They are however insensitive to dihydropyridines (DHP). Calcium channels containing alpha-1E subunit could be involved in the modulation of firing patterns of neurons which is important for information processing.[1]
Publication Abstract from PubMed
High-voltage-activated R-type Ca(V)2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human Ca(V)2.3 in complex with the alpha2delta1 and beta1 subunits. The VSD(II) is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD(II) is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6(II), which is exclusively conserved in the Ca(V)2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5(II) helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca(V)2 channels.
Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca(V)2.3.,Gao Y, Xu S, Cui X, Xu H, Qiu Y, Wei Y, Dong Y, Zhu B, Peng C, Liu S, Zhang XC, Sun J, Huang Z, Zhao Y Nat Commun. 2023 Jan 31;14(1):516. doi: 10.1038/s41467-023-36260-2. PMID:36720859[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Heron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N, Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub , 2018 Oct 18. PMID:30343943 doi:http://dx.doi.org/10.1016/j.ajhg.2018.09.006
↑ Gao Y, Xu S, Cui X, Xu H, Qiu Y, Wei Y, Dong Y, Zhu B, Peng C, Liu S, Zhang XC, Sun J, Huang Z, Zhao Y. Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca(V)2.3. Nat Commun. 2023 Jan 31;14(1):516. PMID:36720859 doi:10.1038/s41467-023-36260-2
