8epm | pdb_00008epm
Human R-type voltage-gated calcium channel Cav2.3 CH2II-deleted mutant at 3.1 Angstrom resolution
Structural highlights
DiseaseCAC1E_HUMAN The disease is caused by variants affecting the gene represented in this entry. FunctionCAC1E_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 PubMedThe 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. See AlsoReferences
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