ABCMdb

PMID: 23055971

Molinski S, Eckford PD, Pasyk S, Ahmadi S, Chin S, Bear CE
Functional Rescue of F508del-CFTR Using Small Molecule Correctors.
Front Pharmacol. 2012 Sep 26;3:160. doi: 10.3389/fphar.2012.00160. eCollection 2012., [PubMed]

Sentences

No. Mutations Sentence Comment

34 ABCC7 p.Arg553Gln ABCC7 p.Arg555Lys ABCC7 p.Phe494Asn ABCC7 p.Gln637Arg ABCC7 p.Gly550Arg The first stabilizing mutations were identified in the ABC conserved, canonical subdomains, and cluster in the b1;-helical subdomain (G550R, R553Q, R555K), in the b3; switch (F494N), and ATP binding core subdomain (Q637R). Login to comment 53 ABCC7 p.Leu1065Pro ABCC7 p.Arg1066Cys ABCC7 p.Gly1069Arg Disease-causing mutations in the coupling helix of ICL4 that cause ER retention have been described (L1065P, R1066C, and G1069R), supporting the idea that this region mediates important interactions during folding (Mendoza et al., 2012). Login to comment 54 ABCC7 p.Arg1070Trp ABCC7 p.Arg1070Trp Substitution of the arginine at position 1070 with tryptophan (R1070W) in the context of the Wt-CFTR, introduces a bulky group on the face of the coupling helix that interacts with NBD1 and like the substitutions above, this leads to misprocessing. Login to comment 58 ABCC7 p.Arg1070Trp ABCC7 p.Val510Asp Introduction of R1070W or V510D in the F508del-CFTR protein partially corrects folding of the full-length protein, highlighting the idea that even in the absence of F508, assembly of the CFTR can be partially restored through structural changes at key loci in the protein (Thibodeau et al., 2010; Mendoza et al., 2012). Login to comment 59 ABCC7 p.Arg553Gln ABCC7 p.Gly550Glu ABCC7 p.Arg555Lys Similarly, the second site mutations, previously discussed with regard to their efficacy in stabilizing the isolated F508del-NBD1, i.e., the second site mutations in the ABC conserved core ATP binding subdomains (G550E, R553Q, and R555K) also promote improved processing of the full-length F508del-CFTR. Login to comment 60 ABCC7 p.Ile539Thr Similarly, second site mutations in unique, flexible regions of NBD1 (i.e., I539T) partially correct the processing defect in F508del-CFTR. Login to comment 62 ABCC7 p.Ile539Thr ABCC7 p.Gly550Glu ABCC7 p.Arg553Met ABCC7 p.Arg555Lys Employing biophysical methods, including circular dichroism, dynamic light scattering,and fluorescence,both groups confirmed that the introduction of "stabilizing mutations" residing in the ABC b1;-helical subdomain (G550E, R553M, R555K) and the structural diverse region (I539T), fully corrects defects in kinetic and thermal stability of the isolated F508del-NBD1 domain. Login to comment 64 ABCC7 p.Arg1070Trp However, in combination with R1070W, a mutation that reconstitutes a more Wt-like ICL4: NBD1 interface, the NBD1-"stabilizing" mutants mediate full correction and near normal processing. Login to comment 172 ABCC7 p.Val232Asp Corr-4a has a mild correction effect of the F508del-CFTR (effective in the low &#b5;M range), and a nearly complete correction effect on the rare mutant V232D-CFTR (Caldwell et al., 2011). Login to comment 360 ABCC7 p.Gly551Asp This is in contrast to the dramatic improvement of G551D-CFTR patients upon treatment with VX-770 (Ramsey et al., 2011). Login to comment 361 ABCC7 p.Gly551Asp The G551D-CFTR protein traffics normally to the cell surface and is thought to have a typicalWt residence time,but lacks any CFTR channel function. Login to comment 362 ABCC7 p.Gly551Asp VX-770 increases the channel open probability of normally trafficked Wt-,G551D-,and F508del-CFTR at the cell surface (Van Goor et al., 2009). Login to comment