ABCMdb

ABCC7 p.Thr1057Cys

ClinVar:	c.3169A>G , p.Thr1057Ala ? , not provided
CF databases:	c.3169A>G , p.Thr1057Ala (CFTR1) ? , T1057A was found in a fetus.
Predicted by SNAP2:	A: N (57%), C: D (63%), D: D (66%), E: D (80%), F: D (91%), G: D (66%), H: D (85%), I: D (66%), K: D (80%), L: D (71%), M: D (75%), N: N (53%), P: D (75%), Q: D (59%), R: D (91%), S: N (82%), V: D (66%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: N, Y: N,

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Publications
[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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90 Cys pair cross-linking experiments showed that indeed E543C could be cross-linked with both T966C (CL3) and T1057C (CL4, Fig. 2B), while D1341C was in close contact with both L172C (CL1) and N268C (CL2, Fig. 2C). Login to comment
101 B, T966C/E543C at the CL3/NBD1 interface and T1057C/E543C at the CL4/NBD1 interface at the X-loop of NBD1. Login to comment
142 To determine whether the interfacial interaction of Glu-543 with CL3 and CL4 was indeed affected by PKA phosphorylation, membrane vesicles from HEK cells overexpressing Cys-less CFTR with Cys pairs E543C/T966C and E543C/T1057C were pretreated with PKA in the presence of ATP and Mg2ϩ before cross-linking with various MTS reagents. Login to comment
143 As shown in Fig. 4A, similar to the experiments with whole cells in membranes not treated with PKA, the Cys pairs E543C/T966C and E543C/T1057C were cross-linked by all the MTS reagents tested. Login to comment