ABCC7 p.Tyr1307Cys
| ClinVar: |
c.3921T>A
,
p.Tyr1307*
?
, not provided
c.3920A>G , p.Tyr1307Cys ? , not provided |
| CF databases: |
c.3920A>G
,
p.Tyr1307Cys
(CFTR1)
?
, This change has been detected by DGGE analysis and direct sequencing.
|
| Predicted by SNAP2: | A: N (57%), C: N (66%), D: D (85%), E: D (71%), F: N (97%), G: D (71%), H: N (87%), I: D (53%), K: D (80%), L: N (87%), M: N (66%), N: N (78%), P: D (85%), Q: D (71%), R: D (75%), S: D (75%), T: D (66%), V: N (78%), W: D (63%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: N, F: N, G: D, H: N, I: N, K: D, L: N, M: N, N: N, P: D, Q: N, R: N, S: N, T: N, V: D, W: N, |
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[hide] Polymorphisms of MRP1 (ABCC1) and related ATP-depe... Pharmacogenet Genomics. 2005 Aug;15(8):523-33. Conseil G, Deeley RG, Cole SP
Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters.
Pharmacogenet Genomics. 2005 Aug;15(8):523-33., [PMID:16006996]
Abstract [show]
Genetic variations in drug metabolizing enzymes and targets are established determinants of adverse drug reactions and interactions, but less is known about the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a distinctive pattern of tissue expression and substrate specificity. Together, these five transporters play important roles in the disposition and elimination of drugs and other organic anions, and in maintenance of blood-tissue barriers, as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, corresponding to a human condition known as Dubin-Johnson syndrome (DJS). Naturally occurring mutations in MRP/ABCC-related drug transporters have been reported, some of which are non-synonymous single nucleotide polymorphisms. The consequences of the resulting amino acid changes can sometimes be predicted from in vitro site-directed mutagenesis studies or from knowledge of mutations of analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of sequence variants and haplotype analysis, together with in vitro biochemical validation assays and pharmacological studies in knockout animals, should make it possible to determine how genetic variation in the MRP-related transporters contributes to the range of responses to drugs and chemicals observed in different human populations.
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No. Sentence Comment
56 In the kidney, glomeruli and distal collecting tubules express MRP1, and, in the brain, MRP1 appears to form part of the drug permeability barrier Fig. 1 CF (CFTR/ABCC7) Q1291R E1228G Q1238R G1244E/V G1247R G1249R S1251N S1255P/L W1282G/R/C R1283K/M N1303K Y1307C E1321Q K1351E Q1352H R1268Q V1298F T1301I G1302R A1303P R1314W/Q G1321S R1339C Q1347H I1350L G1354R D1361N Q1382R A1450T R1347E R1351P V1359G/M S1368A G1377R G1382S R1392H R1419C R1435Q G1477R G1479R R1492W E1505K DJS (MRP2/ABCC2) NBD1 NBD2 COOH MEMBRANE MSD MSD MSD 12131415161710116 7 8 91 23 4 5TM H2 N Extracellular Intracellular PXE (ABCC6) PHHI (SUR1/ABCC8) Two-dimensional structure of MRP-related proteins.
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ABCC7 p.Tyr1307Cys 16006996:56:257
status: NEW[hide] Nucleotide binding domains of human CFTR: a struct... Cell Mol Life Sci. 2005 Sep;62(18):2112-23. Eudes R, Lehn P, Ferec C, Mornon JP, Callebaut I
Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations.
Cell Mol Life Sci. 2005 Sep;62(18):2112-23., [PMID:16132229]
Abstract [show]
Defective function of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) causes CF, the most frequent lethal inherited disease among the Caucasian population. The structure of this chloride ion channel includes two nucleotide-binding domains (NBDs), whose ATPase activity controls channel gating. Recently, the experimental structures of mouse and human CFTR NBD1 and our model of the human CFTR NBD1/NBD2 heterodimer have provided new insights into specific structural features of the CFTR NBD dimer. In the present work, we provide a structural classification of CF-causing mutations which may complement the existing functional classification. Our analysis also identified amino acid residues which may play a critical role in interdomain interaction and are located at the NBD1-NBD2 interface or on the surface of the dimer. In particular, a cluster of aromatic amino acids, which includes F508 and straddles the two NBDs, might be directly involved in the interaction of the NBD1/NBD2 heterodimer with the channel-forming membrane-spanning domains.
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No. Sentence Comment
247 (B) Ribbon representation of the NBD aa1 - aa2 segment of the three experimental MalK structures and of mCFTR NBD1, with the CFTR F508 and MalK F98 being shown in atomic details involves the exposed F508 residue, only a few missense mutations affecting these exposed aromatic residues have been reported: H484R, Y515H, H620P, H620Q and Y1307C (http://www.genet.sickkids.on.ca/cftr).
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ABCC7 p.Tyr1307Cys 16132229:247:339
status: NEW[hide] Multiple membrane-cytoplasmic domain contacts in t... J Biol Chem. 2008 Sep 26;283(39):26383-90. Epub 2008 Jul 25. He L, Aleksandrov AA, Serohijos AW, Hegedus T, Aleksandrov LA, Cui L, Dokholyan NV, Riordan JR
Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating.
J Biol Chem. 2008 Sep 26;283(39):26383-90. Epub 2008 Jul 25., 2008-09-26 [PMID:18658148]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ATP-binding cassette (ABC) ion channel mutated in patients with cystic fibrosis. The most common mutation, deletion of phenylalanine 508 (DeltaF508) and many other disease-associated mutations occur in the nucleotide binding domains (NBD) and the cytoplasmic loops (CL) of the membrane-spanning domains (MSD). A recently constructed computational model of the CFTR three-dimensional structure, supported by experimental data (Serohijos, A. W., Hegedus, T., Aleksandrov, A. A., He, L., Cui, L., Dokholyan, N. V., and Riordan, J. R. (2008) Proc. Natl. Acad. Sci. U. S. A. 105, 3256-3261) revealed that several of these mutations including DeltaF508 disrupted interfaces between these domains. Here we have used cysteine cross-linking experiments to verify all NBD/CL interfaces predicted by the structural model and observed that their cross-linking has a variety of different effects on channel gating. The interdomain contacts comprise aromatic clusters important for stabilization of the interfaces and also involve the Q-loops and X-loops that are in close proximity to the ATP binding sites. Cross-linking of all domain-swapping contacts between NBDs and MSD cytoplasmic loops in opposite halves of the protein rapidly and reversibly arrest single channel gating while those in the same halves have lesser impact. These results reinforce the idea that mediation of regulatory signals between cytoplasmic- and membrane-integrated domains of the CFTR channel apparently relies on an array of precise but highly dynamic interdomain structural joints.
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No. Sentence Comment
75 To verify these specific interactions, we performed cross-linking experiments in HEK cells expressing a Cys-less CFTR construct containing the Cys pair 276C and Y1307C (Fig. 2A).
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ABCC7 p.Tyr1307Cys 18658148:75:161
status: NEW100 A, 276C/Y1307C and N268C/F1292C at the CL2/NBD2 interface involving an aromatic cluster and the Q-loop.
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ABCC7 p.Tyr1307Cys 18658148:100:8
status: NEW