REAL

Asymmetry of movements in CFTR's two ATP sites during pore opening serves their distinct functions

Sorum, Ben and Törőcsik, Beáta and Csanády, László (2017) Asymmetry of movements in CFTR's two ATP sites during pore opening serves their distinct functions. ELIFE, 6. pp. 1-17. ISSN 2050-084X

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Abstract

CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, is opened by ATP binding to two cytosolic nucleotide binding domains (NBDs), but pore-domain mutations may also impair gating. ATP-bound NBDs dimerize occluding two nucleotides at interfacial binding sites; one site hydrolyzes ATP, the other is inactive. The pore opens upon tightening, and closes upon disengagement, of the catalytic site following ATP hydrolysis. Extent, timing, and role of non-catalytic-site movements are unknown. Here we exploit equilibrium gating of a hydrolysis-deficient mutant and apply Phi value analysis to compare timing of opening-associated movements at multiple locations, from the cytoplasmic ATP sites to the extracellular surface. Marked asynchrony of motion in the two ATP sites reveals their distinct roles in channel gating. The results clarify the molecular mechanisms of functional cross-talk between canonical and degenerate ATP sites in asymmetric ABC proteins, and of the gating defects caused by two common CF mutations.

Item Type: Article
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 16 Aug 2018 12:26
Last Modified: 16 Aug 2018 12:26
URI: http://real.mtak.hu/id/eprint/82731

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