5y7l | pdb_00005y7l
Solution structure of Hbeta4 extracellular loop of BK potassium channel
Structural highlights
Function[KCMB4_HUMAN] Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Decreases the gating kinetics and calcium sensitivity of the KCNMA1 channel, but with fast deactivation kinetics. May decrease KCNMA1 channel openings at low calcium concentrations but increases channel openings at high calcium concentrations. Makes KCNMA1 channel resistant to 100 nM charybdotoxin (CTX) toxin concentrations.[1] [2] [3] Publication Abstract from PubMedLarge-conductance Ca(2+)- and voltage-dependent K(+) (BK) channels display diverse biological functions while their pore-forming alpha subunit is coded by a single Slo1 gene. The variety of BK channels is correlated with the effects of BKalpha coexpression with auxiliary beta (beta1-beta4) subunits, as well as newly defined gamma subunits. Charybdotoxin (ChTX) blocks BK channel through physically occluding the K(+)-conduction pore. Human brain enriched beta4 subunit (hbeta4) alters the conductance-voltage curve, slows activation and deactivation time courses of BK channels. Its extracellular loop (hbeta4-loop) specifically impedes ChTX to bind BK channel pore. However, the structure of beta4 subunit's extracellular loop and the molecular mechanism for gating kinetics, toxin sensitivity of BK channels regulated by beta4 are still unclear. To address them, here, we first identified four disulfide bonds in hbeta4-loop by mass spectroscopy and NMR techniques. Then we determined its three-dimensional solution structure, performed NMR titration and electrophysiological analysis, and found that residue Asn123 of beta4 subunit regulated the gating and pharmacological characteristics of BK channel. Finally, by constructing structure models of BKalpha/beta4 and thermodynamic double-mutant cycle analysis, we proposed that BKalpha subunit might interact with beta4 subunit through the conserved residue Glu264(BKalpha) coupling with residue Asn123(beta4). Solution structure of extracellular loop of human beta4 subunit of BK channel and its biological implication on ChTX sensitivity.,Wang Y, Lan W, Yan Z, Gao J, Liu X, Wang S, Guo X, Wang C, Zhou H, Ding J, Cao C Sci Rep. 2018 Mar 15;8(1):4571. doi: 10.1038/s41598-018-23016-y. PMID:29545539[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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