ATP-independent CFTR channel gating and allosteric modulation by phosphorylation.

Proceedings of the National Academy of Sciences of the United States of America
Wei WangKevin Kirk

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel, an ATP binding cassette (ABC) transporter. CFTR gating is linked to ATP binding and dimerization of its two nucleotide binding domains (NBDs). Channel activation also requires phosphorylation of the R domain by poorly understood mechanisms. Unlike conventional ligand-gated channels, CFTR is an ATPase for which ligand (ATP) release typically involves nucleotide hydrolysis. The extent to which CFTR gating conforms to classic allosteric schemes of ligand activation is unclear. Here, we describe point mutations in the CFTR cytosolic loops that markedly increase ATP-independent (constitutive) channel activity. This finding is consistent with an allosteric gating mechanism in which ligand shifts the equilibrium between inactive and active states but is not essential for channel opening. Constitutive mutations mapped to the putative symmetry axis of CFTR based on the crystal structures of related ABC transporters, a common theme for activating mutations in ligand-gated channels. Furthermore, the ATP sensitivity of channel activation was strongly enhanced by these constitutive mutations, as predicted for an allosteric ...Continue Reading

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Sep 2, 2010·The Journal of General Physiology·Yonghong BaiTzyh-Chang Hwang
Nov 29, 2011·Protein Engineering, Design & Selection : PEDS·Michelle McClureStephen Barnes
Nov 5, 2014·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Yassine El Hiani, Paul Linsdell
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Oct 15, 2021·The Journal of General Physiology·Daniel T InfieldNael A McCarty

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