ABCA1 p.Arg1068Trp
| Predicted by SNAP2: | A: D (85%), C: D (91%), D: D (95%), E: D (91%), F: D (95%), G: D (91%), H: D (85%), I: D (91%), K: D (85%), L: D (91%), M: D (80%), N: D (91%), P: D (95%), Q: D (85%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Homology modeling and functional testing of an ABC... Atherosclerosis. 2011 Oct;218(2):404-10. Epub 2011 Jun 29. Suetani RJ, Sorrenson B, Tyndall JD, Williams MJ, McCormick SP
Homology modeling and functional testing of an ABCA1 mutation causing Tangier disease.
Atherosclerosis. 2011 Oct;218(2):404-10. Epub 2011 Jun 29., [PMID:21763656]
Abstract [show]
OBJECTIVE: To investigate the impact of the p.R1068H mutation on the structure and function of the ATP-binding cassette A1 (ABCA1) protein. METHODS: A homology model of the nucleotide binding domains of ABCA1 was constructed to identify the three-dimensional orientation of R1068. Cholesterol efflux assays were performed on fibroblasts obtained from members of a Tangier disease (TD) family carrying the p.R1068H mutation and in HEK293 cells transfected with a p.R1068H mutant cDNA vector. Confocal microscopy was used to investigate the localisation of the wildtype and mutant p.R1068H protein in HEK293 cells. RESULTS: Sequence alignments and modeling indicated residue R1068 to be located in an alpha-helix downstream of the Walker B motif in the first nucleotide binding domain (NBD-1), in a position to form ionic interactions with D1092 and E1093. Cholesterol efflux studies showed the efflux from TD fibroblasts and HEK293 cells expressing the mutant p.R1068H protein to be markedly reduced compared to wildtype. Localisation of the mutant p.R1068H protein in HEK293 cells showed intracellular retention of the protein indicating a defect in trafficking to the plasma membrane. CONCLUSION: Homology modeling of the ABCA1 protein showed that the p.R1068H mutation would likely disrupt the conformation of NBD-1. Functional studies of p.R1068H showed a lack of cholesterol efflux function due to defective trafficking to the plasma membrane, most likely caused by impaired oligomerisation.
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No. Sentence Comment
137 Indeed, SIFT predicts any residue substitution at position 1068 to be tolerated except R1068W which does not align with the observation that p.R1068H and the p.R1068C mutation are associated with extremely reduced HDL levels [11,23].
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ABCA1 p.Arg1068Trp 21763656:137:87
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