7xqi
Hemichannel-focused structure of C-terminal truncated connexin43/Cx43/GJA1 gap junction intercellular channel in POPE nanodiscs (FIN conformation)
Structural highlights
DiseaseCXA1_HUMAN Autosomal recessive non-syndromic sensorineural deafness type DFNB;Hypoplastic left heart syndrome;Oculodentodigital dysplasia;Craniometaphyseal dysplasia;Syndactyly type 3. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease may be caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionCXA1_HUMAN Gap junction protein that acts as a regulator of bladder capacity. A gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract (By similarity). Publication Abstract from PubMedConnexin family proteins assemble into hexameric hemichannels in the cell membrane. The hemichannels dock together between two adjacent membranes to form gap junction intercellular channels (GJIChs). We report the cryo-electron microscopy structures of Cx43 GJICh, revealing the dynamic equilibrium state of various channel conformations in detergents and lipid nanodiscs. We identify three different N-terminal helix conformations of Cx43-gate-covering (GCN), pore-lining (PLN), and flexible intermediate (FIN)-that are randomly distributed in purified GJICh particles. The conformational equilibrium shifts to GCN by cholesteryl hemisuccinates and to PLN by C-terminal truncations and at varying pH. While GJIChs that mainly comprise GCN protomers are occluded by lipids, those containing conformationally heterogeneous protomers show markedly different pore sizes. We observe an alpha-to-pi-helix transition in the first transmembrane helix, which creates a side opening to the membrane in the FIN and PLN conformations. This study provides basic structural information to understand the mechanisms of action and regulation of Cx43 GJICh. Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM.,Lee HJ, Cha HJ, Jeong H, Lee SN, Lee CW, Kim M, Yoo J, Woo JS Nat Commun. 2023 Feb 18;14(1):931. doi: 10.1038/s41467-023-36593-y. PMID:36805660[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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