ABCMdb

PMID: 19332488

Hwang TC, Sheppard DN
Gating of the CFTR Cl- channel by ATP-driven nucleotide-binding domain dimerisation.
J Physiol. 2009 May 15;587(Pt 10):2151-61. Epub 2009 Mar 30., 2009-05-15 [PubMed]

Sentences

No. Mutations Sentence Comment

32 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp The location of the CF mutations G551D (site 2), G1349D (site 1) and F508del (surface of NBD1 opposing ICL4) are shown. Login to comment 66 ABCC7 p.Trp401Gly ABCC7 p.Tyr1219Gly The mutant Y1219G-CFTR, but not W401G-CFTR, exhibited a dramatic rightward shift of the relationship between [ATP] and the opening rate of the CFTR Cl-channel. Login to comment 93 ABCC7 p.Gly551Asp By accelerating channel opening and slowing channel closure, 2 -deoxy-ATP robustly enhances the activity of G551D-CFTR, a CF mutant with a profound defect in channel gating (see below, the section Contribution of the LSGGQ motifs to ATP-binding sites, Fig. 4 and Cai et al. Figure 4. Login to comment 94 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp 2 -Deoxy-ATP potentiates strongly the single-channel activity of wild-type and G551D-CFTR A and B, representative recordings of wild-type and G551D-CFTR Cl-channels in excised inside-out membrane patches in the presence of either ATP (1 mM) or 2 -deoxy-ATP (2 -dATP; 1 mM). Login to comment 115 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp The functional importance of the LSGGQ motifs in CFTR is attested by the many disease-associated mutations found in these regions of the protein (www.genet.sickkids.on.ca/cftr), most notably G551D and G1349D (Cai et al. 2006; Bompadre et al. 2007). Login to comment 117 ABCC7 p.Gly551Asp Of special note, the CF mutation G551D causes a profound defect in channel gating (Fig. 4B) and abolishes the ATP dependence of the CFTR Cl-channel (Bompadre et al. 2007, 2008). Login to comment 119 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Cys ABCC7 p.Gly551Cys Recently, Wang et al. (2009) demonstrated that cadmium (Cd2+ ) can act as a ligand to gate G551Dand G551C-CFTR by serving as a metal bridge connecting G551D/C to an unknown cysteine residue in CFTR. Login to comment 157 ABCC7 p.Gly551Asp Moreover, binding of either 2 -deoxy-ATP or P-ATP at ATP-binding site 1 augments the activity of G551D-CFTR (Fig. 4) (Cai et al. 2006; Bompadre et al. 2008), raising the possibility that this binding site might be used as a molecular target for the development of rational new therapies for CF. Login to comment 158 ABCC7 p.Gly551Asp Since two aromatic amino acids, F409 and F430, in the 'regulatory insertion` (RI, a ~30 amino acid mobile region located at the N-terminus of NBD1; Lewis et al. 2004, 2005) may also help stabilise nucleotide binding in site 1 (Zhou et al. 2006), the RI might play a critical role in mediating the effects of P-ATP on G551D-CFTR channel gating. Login to comment