ABCMdb

PMID: 23457292

Chong PA, Kota P, Dokholyan NV, Forman-Kay JD
Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability.
Cold Spring Harb Perspect Med. 2013 Mar 1;3(3):a009522. doi: 10.1101/cshperspect.a009522., [PubMed]

Sentences

No. Mutations Sentence Comment

96 ABCC7 p.Val510Asp The V510D mutation likely introduces a salt bridge with R1070, strengthening this interface. Login to comment 98 ABCC7 p.Arg1070Trp ABCC7 p.Val510Arg ABCC7 p.Arg1070Asp Similar results are seen with an R1070W mutation, which might be expected to enhance the hydrophobic contacts at this interface or fill the void introduced by deletion of F508, or with a combined R1070D/V510R mutation, which would reverse the proposed salt bridge (Farinha et al. 2010; Loo et al. 2010). Login to comment 99 ABCC7 p.Val510Asp These additional mutations support the idea that the F508del phenotype can be attributed at least partially to a disruption of this interface, although as we discuss below, the V510D mutation also thermodynamically stabilizes NBD1 itself. Login to comment 100 ABCC7 p.Val510Asp The data on the V510D mutation indicate that interdomain interactions between NBD1 and ICL4 are required for proper folding and maturation of CFTR. Login to comment 200 ABCC7 p.Arg553Gln ABCC7 p.Gly550Glu ABCC7 p.Arg555Lys Many of the suppressor mutations, like G550E, R553Q, and R555K (Teem et al. 1993, 1996), which are relatively distant from the F508 position, increase NBD1 thermal stability and reverse some of the processing and functional defects, presumably without reverting the surface changes caused by deletion of F508. Login to comment 201 ABCC7 p.Val510Asp V510D, which may rescue F508del by facilitating the NBD1-ICL4 interaction, also stabilizes NBD1 (Protasevich et al. 2010), suggesting a dual mechanism of action. Login to comment 202 ABCC7 p.Ile539Thr Recently, substitution of proline residues at key positions in the Q-loop, the SDR, and the RI in context of the I539T suppressor mutation has been shown to restore channel function and thermostability to full-length F508del CFTR. Login to comment