ABCMdb

PMID: 25287046

Mornon JP, Hoffmann B, Jonic S, Lehn P, Callebaut I
Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics.
Cell Mol Life Sci. 2015 Apr;72(7):1377-403. doi: 10.1007/s00018-014-1749-2. Epub 2014 Oct 7., [PubMed]

Sentences

No. Mutations Sentence Comment

308 ABCC7 p.Phe508Cys ABCC7 p.Tyr1073Cys Of note, a perfect theoretical disulfide bridge in the double mutant F508C/Y1073C should be possible in this particular conformer [Online Resource 21 (B)]. Login to comment 309 ABCC7 p.Phe508Cys ABCC7 p.Phe508Cys ABCC7 p.Glu1371Ser The existence of the alternative position of F508 was further supported by the fact that the modification of F508C by benzyl-methanethiosulfonate (MTSBn), conserving the F508 aromatic character and restoring gating activity (lost for the F508C mutation in the open state-locked E1371S variant) [76], can be accommodated in both the initial and MD-generated models of CFTR [Online Resource 21 (A)]. Login to comment 346 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg352Gln ABCC7 p.Pro205Ser ABCC7 p.Gly85Glu ABCC7 p.Thr338Ile ABCC7 p.Glu92Lys ABCC7 p.Ile336Lys ABCC7 p.Asp110His ABCC7 p.Ser341Pro First, almost all CF-causing mutations involving residues located in the MSD transmembrane segments are encountered in MSD1 and generally concern positions lining the pore (G85E, E92K, D110H, P205S, R334W, I336K, T338I, S341P, R347H/R347P, and R352Q) (Fig. 7a). Login to comment 348 ABCC7 p.Pro205Ser ABCC7 p.Leu206Trp ABCC7 p.His199Tyr In addition, L206W and H199Y are situated nearby P205S, orientated toward the lipid bilayer. Login to comment 349 ABCC7 p.Pro67Leu P67L lies in the loop between the N-terminal segment and the N-helix. Login to comment 350 ABCC7 p.Arg74Trp R74W (which is reported to be of varying clinical consequence) is located in the vicinity of a large aromatic cluster, including F77, F78, W79, F81, F83, and Y84; the substitution of this arginine by a tryptophan might thus destabilize the local geometry. Login to comment 351 ABCC7 p.Met1101Lys ABCC7 p.Leu927Pro As already hinted to above, only two mutations are observed in MSD2, L927P, and M1101K, which both might disturb the conformation and behavior of the transmembrane helices within the lipid bilayer. Login to comment 352 ABCC7 p.Arg117His ABCC7 p.Arg117Cys Interestingly, amino acid R117, which is involved in the mutations R117C and R117H and is located in the first extracellular loop (ECL1) at the very beginning of TM2, can make a salt bridge with E1124 in ECL6 (distances of 5.5 and 5.8 A da; ) and might thus, among others, participate in the stabilization of the open form of the channel (Fig. 7b). Login to comment 353 ABCC7 p.Arg117His ABCC7 p.Arg117Cys The R117H mutation (varying clinical consequence) appears less severe than R117C (CF-causing), as histidine probably retains part of the attraction with the glutamate E1124 situated at 7.9 A da; . Login to comment 354 ABCC7 p.Arg334Trp ABCC7 p.Asp110His Finally, two CF-causing mutations involve amino acids which are implied in salt bridges: (1) D110 in TM2 (mutation D110H; salt bridge with R1128, distances of 4.0 and 5.0 A da; ) and (2) R334 in ECL3 (mutation R334W; salt bridge with D891, distances of 3.8 and 4.4 A da; ) (Fig. 7b). Login to comment 355 ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg ABCC7 p.Gly178Glu Second, CF-causing mutations in the ICLs involve residues located at the base of the four-helix bundle assembling the four internal ICL helices (symmetric positions in ICL1 (G178E G178R) and ICL3 (G970R), which cannot be substituted by any other amino acid because of steric hindrance reasons (Fig. 7c; Online Resource 2). Login to comment 356 ABCC7 p.Ser945Leu S945L lies within the main lateral tunnel, and might thus impair access to the pore. Login to comment 357 ABCC7 p.Val520Phe ABCC7 p.Arg560Thr ABCC7 p.Leu1065Pro ABCC7 p.Arg1066Cys ABCC7 p.Leu1077Pro ABCC7 p.Phe1074Leu ABCC7 p.Arg1066His ABCC7 p.Arg560Lys ABCC7 p.Ser492Phe ABCC7 p.Ala559Thr ABCC7 p.His1054Asp ABCC7 p.Gly1061Arg ABCC7 p.Ala561Glu Moreover, a large ''hot spot`` region for natural CFTR mutations is located at the NBD1:ICL4 interface, involving (1) six ICL4 positions (H1054D, G1061R, L1065P, R1066H/R1066C, F1074L, and L1077P), which line the path followed by F508 during the MD1 conformational transition from its initial to its final position, and (2) seven positions in NBD1 (S492F, I507del, F508del, V520F, A559T, R560K/R560T, and A561E) (Fig. 7c). Login to comment 358 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg Some other CFTR mutations of varying clinical consequences, such as F1052 V, G1069R, and R1070W/R1070Q complete the list in this region. Login to comment 359 ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Ser1255Pro ABCC7 p.Ser1251Asn ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn Third, at the level of the NBD1:NBD2 heterodimer, CF-causing mutations are concentrated within the canonical ATP-binding site (S549N, S549R, G551D/G551S, G1244E, S1251N, and S1255P) (Fig. 7d). Login to comment 360 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Asn1303Lys ABCC7 p.Leu467Pro The effects of remaining mutations listed in CFTR2 database can also be well understood in light of our structural data: (1) A455E has indeed no room to be well adapted, (2) G1244E (mentioned above) also occurs in a well conserved position (position 23 in Online Resource 2), (3) L467P might disturb the helix in which it is included, (4) G1349D is in the non-canonical ATP-binding site and, alike its corresponding G551D, has no room to be well adapted in presence of ATP, and finally (5) N1303K might disturb the large Q-loop of the NBD2 a-helical subdomain (position 42 in Online Resource 1 and Online Resource 2). Login to comment 362 ABCC7 p.Ile1027Thr I1027T faces lipids, but its hydroxyl group likely hides its polarity by establishing a H-bond with the V1024 carbonyl group, within the same helix. Login to comment