Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization

Mihalyi, C [Mihályi, Csaba (biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Torocsik, B [Törőcsik, Beáta (orvosi biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Csanady, L ✉ [Csanády, László (Biokémia), szerző] MTA-SE Lendület Ioncsatorna Kutatócsoport (SE / AOK / I / BMBI / BT)

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: ELIFE 2050-084X 5 Paper: e18164 , 12 p. 2016
  • SJR Scopus - Biochemistry, Genetics and Molecular Biology (miscellaneous): D1
Azonosítók
Szakterületek:
    In CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) opens the pore, and dimer disruption following ATP hydrolysis closes it. Spontaneous openings without ATP are rare in wild-type CFTR, but in certain CF mutants constitute the only gating mechanism, stimulated by ivacaftor, a clinically approved CFTR potentiator. The molecular motions underlying spontaneous gating are unclear. Here we correlate energetic coupling between residues across the dimer interface with spontaneous pore opening/closure in single CFTR channels. We show that spontaneous openings are also strictly coupled to NBD dimerization, which may therefore occur even without ATP. Coordinated NBD/pore movements are therefore intrinsic to CFTR: ATP alters the stability, but not the fundamental structural architecture, of open- and closed-pore conformations. This explains correlated effects of phosphorylation, mutations, and drugs on ATP-driven and spontaneous activity, providing insights for understanding CF mutation and drug mechanisms.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2021-11-29 13:49