ABCC7 p.Ser222Ala
| Predicted by SNAP2: | A: N (53%), C: D (71%), D: D (80%), E: D (85%), F: D (66%), G: D (66%), H: D (85%), I: D (71%), K: D (85%), L: D (80%), M: D (80%), N: N (66%), P: D (85%), Q: D (80%), R: D (85%), T: N (57%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, T: N, 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
82 For example, the point mutations Q220A, S222A, F224A, and F229A each resulted in species patterns with a more heavily populated dimer band versus the higher order oligomer bands.
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ABCC7 p.Ser222Ala 11888281:82:40
status: NEW[hide] Molecular dissection of the butyrate action reveal... Mol Pharmacol. 2004 Nov;66(5):1248-59. Epub 2004 Aug 10. Sugita M, Kongo H, Shiba Y
Molecular dissection of the butyrate action revealed the involvement of mitogen-activated protein kinase in cystic fibrosis transmembrane conductance regulator biogenesis.
Mol Pharmacol. 2004 Nov;66(5):1248-59. Epub 2004 Aug 10., [PMID:15304546]
Abstract [show]
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which belongs to the superfamily of ATP-binding cassette transporters and uniquely possesses an additional large cytoplasmic domain [regulatory (R) domain]. CFTR inefficiently folds by means of co- and post-translational interactions with the cytosolic chaperones as well as luminal chaperones in the endoplasmic reticulum (ER). Aberrant folding and defective trafficking of the CFTR protein, which functions as an apical membrane Cl(-) channel, is the principal cause of cystic fibrosis. Recent data indicated that butyrate improves CFTR trafficking partly by regulating molecular chaperones; however, the precise mechanism of butyrate action remains elusive. In the present study, we examine the molecular aspect underlying the butyrate action in CFTR biogenesis by evaluating the expression and localization of the green fluorescent protein (GFP)-tagged CFTR transgenes in Cos7 cells. Our data show that butyrate significantly promoted stability of the ER-located form of GFP-wild-type (wt)-CFTR, followed by an increase in the amount of plasma membrane GFP-wt-CFTR. In contrast, the expression of the R domain deletion mutant GFP-DeltaR-CFTR was slightly increased by butyrate. The butyrate action on wt-CFTR expression was partially blocked by PD98059 (2'-amino-3'-methoxyflavone), a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK), which is the upstream activator of extracellular-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Furthermore, activation of ERK/MAPK by the coexpression of constitutively active MAPKK/MEK predominantly augmented the expression of wt-CFTR, but not of DeltaR-CFTR, induced by butyrate. These data suggest that butyrate may facilitate the biogenesis and trafficking of wt-CFTR by requiring the presence of the R domain and further involving active ERK/MAPK in its biogenesis.
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215 In the present study, LA- SDSE-MAPKK, in which Leu33 , Leu37 , Ser218 , and Ser222 were replaced by Ala, Ala, Asp, and Glu, respectively, was used as the constitutively active mutant (Fukuda et al., 1997).
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ABCC7 p.Ser222Ala 15304546:215:76
status: NEW234 We also checked the effect of cotransfection of the dominant-negative construct SASA-MAPKK, in which Ser218 and Ser222 were replaced by Ala (Gotoh et al., 1999); however, the cellular levels of active ERK/MAPKK were significantly reduced by CFTR transfection (Fig. 7A).
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ABCC7 p.Ser222Ala 15304546:234:112
status: NEW