ABCC7 p.Gly226Ala
| Predicted by SNAP2: | A: N (66%), C: D (66%), D: D (80%), E: D (85%), F: D (85%), H: D (85%), I: D (80%), K: D (91%), L: D (71%), M: D (85%), N: D (71%), P: D (85%), Q: D (80%), R: D (91%), S: N (61%), T: D (66%), V: D (75%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Polar residues in membrane domains of proteins: mo... Biochemistry. 2002 Mar 19;41(11):3647-53. Partridge AW, Melnyk RA, Deber CM
Polar residues in membrane domains of proteins: molecular basis for helix-helix association in a mutant CFTR transmembrane segment.
Biochemistry. 2002 Mar 19;41(11):3647-53., 2002-03-19 [PMID:11888281]
Abstract [show]
Polar side chains constitute over 20% of residues in the transmembrane (TM) helices of membrane proteins, where they may serve as hydrogen bond interaction sites for phenotypic polar mutations that arise in membrane protein-related diseases. To systematically explore the structural consequences of H-bonds between TM helices, we focused on TM4 of the cystic fibrosis conductance regulator (CFTR) and its cystic fibrosis- (CF-) phenotypic mutation, V232D, as a model system. Synthetic peptides corresponding to wild-type (TM4-wt) (residues 219-242: LQASAFCGLGFLIVLALFQAGLGR) and mutant (TM4-V232D) sequences both adopt helical structures in SDS micelles and display dimer bands on SDS-PAGE arising from disulfide bond formation via wild-type residue Cys-225. However, the TM4-V232D peptide additionally forms a ladder of noncovalent oligomers, including tetramers, hexamers, and octamers, mediated by a hydrogen bond network involving Asp-Gln side chain-side chain interactions. Ala-scanning mutagenesis of the TM4 sequence indicated that ladder formation minimally required the simultaneous presence of the Cys-225, Asp-232, and Gln-237 residues. As random hydrophobic sequences containing these three residues at TM4 equivalent positions did not oligomerize, specific van der Waals packing interactions between helix side chains were also shown to play a crucial role. Overall, the results suggest that polar mutations in membrane domains, in conjunction with critically positioned polar partner residues, potentially constitute a source of aberrant helix interactions that could contribute to loss of function when they arise in protein transmembrane domains.
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No. Sentence Comment
83 In contrast, the G226A mutation stabilized the oligomer ladder, as evidenced by the presence of additional higher order oligomeric bands corresponding to decamers and dodecamers.
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ABCC7 p.Gly226Ala 11888281:83:17
status: NEW