ABCMdb

PMID: 18597042

Mornon JP, Lehn P, Callebaut I
Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces.
Cell Mol Life Sci. 2008 Aug;65(16):2594-612., [PubMed]

Sentences

No. Mutations Sentence Comment

97 ABCC7 p.Arg553Gln ABCC7 p.Gly550Glu ABCC7 p.Arg555Lys ABCC7 p.Phe429Ser ABCC7 p.Phe409Leu ABCC7 p.Phe433Leu These mutations are actually located outside the NBD1 structure core, in the regulatory insertion (F409L, F429S, F433L) and extension (R667H), or in the signature sequence region (G550E, R553Q, R555K), whose local conformations in the crystal structure and in our model are perfectly superimposable. Login to comment 153 ABCC7 p.Thr351Cys ABCC7 p.Trp1145Cys ABCC7 p.Thr1142Cys ABCC7 p.Thr1142Cys ABCC7 p.Met348Cys ABCC7 p.Trp356Cys Interestingly, it appears that all the CFTR mutants for which disulfide cross-linking was detected (M348C in TM6 and T1142C in TM12; T351C in TM6 and T1142C in TM12; W356C in TM6 and W1145C in TM12) line the chloride channel pore and face each other (Fig. 3A). Login to comment 181 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro This helix contains several basic residues (R334, K335, R347 and R352), mutations of two of them (R334W and R347P) being associated with mild CF characterized by altered pore properties [63]. Login to comment 187 ABCC7 p.Arg347Asp ABCC7 p.Asp924Arg Subsequent mutagenesis work involving acidic residues located in different TM helices has shown that the D924R mutation could complement the R347D mutation, suggesting that these two residues may form a salt bridge. Login to comment 194 ABCC7 p.Thr338Ala ABCC7 p.Phe337Ala Two mutations involving these residues (F337A and T338A) also significantly weakened the glibenclamide-mediated blocking of the channel [69], suggesting a direct interaction between the inhibitor and this region of the pore. Login to comment 205 ABCC7 p.Asp1152His ABCC7 p.Ile1139Val ABCC7 p.Asp1154Gly ABCC7 p.Met1137Val The fact that the CF-causing mutations M1137V, I1139V, D1152H and D1154G also interfere with the proper gating of the chloride channel [71] is in good agreement with such an hypothesis. Login to comment 207 ABCC7 p.Asn1138Ala ABCC7 p.Thr1142Ala Finally, two mutations of TM12 residues that also project towards the pore (N1138A and T1142A, Fig. 3B) were reported to significantly strengthen the glibenclamide block and to abolish its dependence on the extracellular Cl-concentration [69], suggesting that these mutations may alter interactions between glibenclamide and Cl- ions within the pore. Login to comment 209 ABCC7 p.Arg117His The arginine R117 residue in ECL1 has been found to influence the channel properties and, accordingly, the well-known R117H mutation, which is generally associated with mild clinical disease, leads to reduced single-channel properties and open probability [63]. Login to comment 239 ABCC7 p.Val510Asp Interestingly, it was very recently shown that the V510D mutation in the DF508 protein promotes its maturation [72]. Login to comment 240 ABCC7 p.Val510Asp This might be explained by the fact that the V510D mutation may restore the ICL4/NBD1 contacts missing in DF508. Login to comment 241 ABCC7 p.Val510Asp Indeed, as shown in Supplementary Data 6 (http://www.impmc.jussieu.fr/~callebau/CFTR.html), our refined model suggests that two novel, nearly symmetrical contacts [R1070 NH1 - D510 OD1 (3.0 ); R1070 NH1 - D510 OD2 (3.3 )] may appear in V510D DF508. Login to comment 250 ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg G178R (involving ICL1) and G970R (involving ICL3) are two CF-causing mutations. Login to comment 251 ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg The G178R mutant exhibits impaired anion translocation capacity [73] and the G970R mutant is probably involved in obtaining or maintaining the open state of the transporter [74]. Login to comment 254 ABCC7 p.Gly970Ala Indeed, in our CFTR model, substitution of G178 by any other residue results in a steric hindrance with the ICL2 main chain (3.5 between the Ca atoms of G178 and V260), while G970A is the only substitution that might be accommodated without steric incompatibility with ICL4 (4.7 between the Ca atoms of G970 and F1052) (Fig. 7). Login to comment 255 ABCC7 p.Ser945Leu ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg ABCC7 p.Glu193Lys Other CF-associated mutations of interest in ICL1 and ICL3 are (i) E193K, a mutation of an ICL1 residue that exhibits, similarly to G178R, impaired anion translocation capacity [73], and (ii) S945L, H949Yand G970R, which affect ICL3 residues and are probably involved (as G970R) in obtaining or maintaining the open state of the transporter [74]. Login to comment 259 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Trp ABCC7 p.Arg1070Pro Among these, several missense mutations have been observed for the critical R1070 residue (R1070W, R1070Q, R1070P; http:// www.genet.sickkids.on.ca/cftr/), but no functional data are available for them. Login to comment 262 ABCC7 p.Arg297Gln In ICL2, the only missense mutation reported that was characterized at the functional level (R297Q) had little effect on the CFTR chloride channel activity [73]. Login to comment 313 ABCC7 p.Val510Asp This hypothesis is supported by the restoration of DF508 maturation by the V510D mutation [72]. Login to comment