ABCMdb

PMID: 22138491

Lukacs GL, Verkman AS
CFTR: folding, misfolding and correcting the DeltaF508 conformational defect.
Trends Mol Med. 2012 Feb;18(2):81-91. Epub 2011 Dec 3., [PubMed]

Sentences

No. Mutations Sentence Comment

95 ABCC7 p.Val510Asp The cytosolic Nedd4-2 and Fbs1 E3 ligases have also been implicated intheERADofDF508CFTR[58,59].Althoughablationofan E3 ligase or overexpression of a deubiquitinating enzyme were unable to rescue DF508 CFTR processing, perhaps due to the redundancy of the ER quality control machinery, the combination of a second site suppressor mutation (Val510Asp) with inhibition of ubiquitination and exposure to a corrector molecule (Corr-4a) led to the robust maturation of the mutant protein in cell culture models [24,60]. Login to comment 111 ABCC7 p.Gly551Asp Point mutations interfering with the composite ATP binding site can interfere with ATP binding and function without causing significant trafficking defects, as exemplified by the G551D mutation [3,71]. Login to comment 112 ABCC7 p.Asn287Tyr Conversely, trafficking mutants may have no defect in gating function, as illustrated by the N287Y mutation within the second intracellular loop of CFTR in which channel endocytosis from the PM is increased without impairment in channel gating [72]. Login to comment 156 ABCC7 p.Gly551Asp PG-01, as well as the Vertex Pharmaceuticals compound VX-770, also corrects defective channel gating in the CF-causing mutant Gly551Asp CFTR, a CFTR 'gating` mutant that is targeted to the cell PM but has low chloride conductance even after maximal cAMP stimulation [78]. Login to comment 157 ABCC7 p.Gly551Asp VX-770 has shown preliminary efficacy in Phase II clinical trials in CF patients carrying the Gly551Asp mutation [79]. Login to comment 158 ABCC7 p.Gly551Asp Although potentiators may be clinically useful in the relatively small group of CF patients having the Gly551Asp substitution, a potentiator alone is unlikely to have clinical benefit in CF caused by the DF508 mutation both because little DF508 CFTR is expressed at the PM and its conformational defect could be distinct from molecules that have constitutively escaped from the ER or are rescued by correctors. Login to comment