Homology modeling and functional testing of an ABCA1 mutation causing Tangier disease

Suetani, Rachel J., Sorrenson, Brie, Tyndall, Joel D. A., Williams, Michael J. A. and McCormick, Sally P. A. (2011) Homology modeling and functional testing of an ABCA1 mutation causing Tangier disease. Atherosclerosis, 218 2: 404-410. doi:10.1016/j.atherosclerosis.2011.06.019

Author Suetani, Rachel J.
Sorrenson, Brie
Tyndall, Joel D. A.
Williams, Michael J. A.
McCormick, Sally P. A.
Title Homology modeling and functional testing of an ABCA1 mutation causing Tangier disease
Journal name Atherosclerosis   Check publisher's open access policy
ISSN 0021-9150
Publication date 2011-10-01
Sub-type Article (original research)
DOI 10.1016/j.atherosclerosis.2011.06.019
Open Access Status Not Open Access
Volume 218
Issue 2
Start page 404
End page 410
Total pages 7
Place of publication Shannon, Clare, Ireland
Publisher Elsevier Ireland
Language eng
Formatted abstract
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 α-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.
Keyword ABCA1
Cholesterol efflux
Homology modeling
Tangier disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 30 Nov 2015, 21:43:16 EST by Rachel Suetani on behalf of Queensland Brain Institute