ABCMdb

PMID: 18417076

Cheung JC, Kim Chiaw P, Pasyk S, Bear CE
Molecular basis for the ATPase activity of CFTR.
Arch Biochem Biophys. 2008 Aug 1;476(1):95-100. Epub 2008 Apr 8., [PubMed]

Sentences

No. Mutations Sentence Comment

89 ABCC7 p.Gly551Asp The CF disease-causing mutant, G551D-CFTR, disrupts the signature motif of the catalytic site and as expected, exhibits defective ATPase activity [30]. Login to comment 91 ABCC7 p.Glu1371Gln We recently determined that the mutant E1371Q-CFTR retained approximately 30% of the wild type activity [34]. Login to comment 107 ABCC7 p.Arg553Gln ABCC7 p.His667Arg ABCC7 p.Gly550Glu ABCC7 p.Arg555Lys ABCC7 p.Phe429Ser ABCC7 p.Phe409Leu ABCC7 p.Phe433Leu The construct generated had several mutations to increase solubility of the domain (F409L, F429S, F433L, G550E, R553Q, R555K, H667R) in addition to the deletion of F508. Login to comment 124 ABCC7 p.Lys1250Ala ABCC7 p.Glu1371Gln For example, mutations of residues in the catalytic site (Site A, Fig. 1) that decrease ATPase activity, such as mutation of the Walker A lysine residue in NBD2 (K1250A) [29] and mutation of the putative catalytic base: E1371Q leads to a decrease in the rate of channel closing [51,52,55]. Login to comment 129 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp This latter concept is supported by the idea that disruption of the signature motifs in each site, G551D (Site A) and G1349D (Site B) led to differential consequences in gating. Login to comment 130 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp The Site A mutant: G551D completely lacked ATP-dependent opening (and ADP-dependent inhibition) whereas the Site B mutant: G1349D exhibited only partially reduced nucleotide-dependent opening. Login to comment 131 ABCC7 p.Gly1349Asp The partial consequences of G1349D on gating suggest a possible role of Site B in modulating the activity of Site A. Login to comment 132 ABCC7 p.Gly551Asp In support of this idea, an ATP analogue was shown to potentiate defective gating by the G551D-CFTR by binding to Site B [57]. Login to comment 169 ABCC7 p.Gly551Asp Understanding the molecular basis for disease in the case of the common CF-causing mutations; DF508-CFTR and G551D-CFTR The crystal structure of the DF508 hNBD1 reveals that the deletion of F508 causes a change in surface topology near the DF508 mutation site [43] supporting the idea that this mutant lacks proper domain-domain interactions and is misassembled [46]. Login to comment 170 ABCC7 p.Gly551Asp Understanding the molecular basis for disease in the case of the common CF-causing mutations; DF508-CFTR and G551D-CFTR The crystal structure of the DF508 hNBD1 reveals that the deletion of F508 causes a change in surface topology near the DF508 mutation site [43] supporting the idea that this mutant lacks proper domain-domain interactions and is misassembled [46]. Login to comment 171 ABCC7 p.Gly551Asp The crystal structure of the NBD1 homodimer (Fig. 1) showed that the G551 residue within the signature motif does interact with ATP at the NBD1-NBD1 interface, suggesting that the disease-causing mutation G551D will disrupt normal nucleotide binding and interactions at the domain interface (pdb:2pze). Login to comment 172 ABCC7 p.Gly551Asp The crystal structure of the NBD1 homodimer (Fig. 1) showed that the G551 residue within the signature motif does interact with ATP at the NBD1-NBD1 interface, suggesting that the disease-causing mutation G551D will disrupt normal nucleotide binding and interactions at the domain interface (pdb:2pze). Login to comment 175 ABCC7 p.Gly551Asp Models of ATP-dependent gating of the wild type CFTR protein and disruption of this function in the disease-causing mutant: G551D-CFTR. Login to comment 176 ABCC7 p.Gly551Asp Models of ATP-dependent gating of the wild type CFTR protein and disruption of this function in the disease-causing mutant: G551D-CFTR. Login to comment 178 ABCC7 p.Gly551Asp (Right) Model of the mutant G551D-CFTR. Login to comment 179 ABCC7 p.Gly551Asp (Right) Model of the mutant G551D-CFTR. Login to comment