Human R-type voltage-gated calcium channel Cav2.3 at 3.1 Angstrom resolution
Structural highlights
8epl 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
The R-type voltage-gated Ca(2+) (Ca(v)) channels Ca(v)2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson's disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Ca(v)2.3 in complex with alpha2delta-1 and beta3 subunits at an overall resolution of 3.1 A. The structure is nearly identical to that of Ca(v)2.2, with VSD(II) in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSD(II) and the tightly closed pore domain. We also determined the cryo-EM structure of a Ca(v)2.3 mutant in which a Ca(v)2-unique cytosolic helix in repeat II (designated the CH2(II) helix) is deleted. This mutant, named DeltaCH2, still reserves a down VSD(II), but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and DeltaCH2 Ca(v)2.3 show that the CH2(II) helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2(II) helix is not necessary for locking the down state of VSD(II).
Structures of the R-type human Ca(v)2.3 channel reveal conformational crosstalk of the intracellular segments.,Yao X, Wang Y, Wang Z, Fan X, Wu D, Huang J, Mueller A, Gao S, Hu M, Robinson CV, Yu Y, Gao S, Yan N Nat Commun. 2022 Nov 30;13(1):7358. doi: 10.1038/s41467-022-35026-6. PMID:36446785[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
↑ Yao X, Wang Y, Wang Z, Fan X, Wu D, Huang J, Mueller A, Gao S, Hu M, Robinson CV, Yu Y, Gao S, Yan N. Structures of the R-type human Ca(v)2.3 channel reveal conformational crosstalk of the intracellular segments. Nat Commun. 2022 Nov 30;13(1):7358. doi: 10.1038/s41467-022-35026-6. PMID:36446785 doi:http://dx.doi.org/10.1038/s41467-022-35026-6
