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Solution structure of extracellular loop of human β4 subunit of BK channel and its biological implication on ChTX sensitivity.

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Wang Y, Lan W, Yan Z, Gao J, Liu X, Wang S, Guo X, Wang C, Zhou H, Ding J, Cao C
OpenAccess logo Sci Rep 8 4571 (2018)
Cited: 4 times
EuropePMC logo PMID: 29545539

Abstract

Large-conductance Ca2+- and voltage-dependent K+ (BK) channels display diverse biological functions while their pore-forming α subunit is coded by a single Slo1 gene. The variety of BK channels is correlated with the effects of BKα coexpression with auxiliary β (β1-β4) subunits, as well as newly defined γ subunits. Charybdotoxin (ChTX) blocks BK channel through physically occluding the K+-conduction pore. Human brain enriched β4 subunit (hβ4) alters the conductance-voltage curve, slows activation and deactivation time courses of BK channels. Its extracellular loop (hβ4-loop) specifically impedes ChTX to bind BK channel pore. However, the structure of β4 subunit's extracellular loop and the molecular mechanism for gating kinetics, toxin sensitivity of BK channels regulated by β4 are still unclear. To address them, here, we first identified four disulfide bonds in hβ4-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 β4 subunit regulated the gating and pharmacological characteristics of BK channel. Finally, by constructing structure models of BKα/β4 and thermodynamic double-mutant cycle analysis, we proposed that BKα subunit might interact with β4 subunit through the conserved residue Glu264(BKα) coupling with residue Asn123(β4).

Articles - 5y7l mentioned but not cited (1)

  1. Solution structure of extracellular loop of human β4 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 8 4571 (2018)


Articles citing this publication (3)

  1. Molecular structures of the human Slo1 K+ channel in complex with β4. Tao X, MacKinnon R. Elife 8 e51409 (2019)
  2. Three-dimensional structure of Megabalanus rosa Cement Protein 20 revealed by multi-dimensional NMR and molecular dynamics simulations. Mohanram H, Kumar A, Verma CS, Pervushin K, Miserez A. Philos Trans R Soc Lond B Biol Sci 374 20190198 (2019)
  3. Development of charybdotoxin Q18F variant as a selective peptide blocker of neuronal BK(α + β4) channel for the treatment of epileptic seizures. Liu X, Tao J, Zhang S, Lan W, Yao Y, Wang C, Xue H, Ji Y, Li G, Cao C. Protein Sci 31 e4506 (2022)


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