| Research Abstract |
This study was done to understand the molecular mechanism of ATP-dependent transporters involved in cholesterol and lipid homeostasis. ABCA1 mediates release of cellular cholesterol and phospholipid to form high density lipoprotein (HDL). ~The three different mutants in the first extracellular domain of human ABCA1 associated with Tangier disease, R587W, W590S, and Q597R, were examined for their subcellular localization and function by using ABCA1-GFP fusion protein stably expressed in HEK293 cells. Our study suggested that the defect of HILL assembly in R587W and Q597R is due to the impaired localization to PM, while W590S have functional defect other than the initial ATP binding and hydrolysis. Functions of ABCA1 are highly regulated at he transcriptional and post-transcriptional levels, and the synthesized ABCA1 protein turns over rapidly with a half-life of 1-2 hours. To examine if functions of ABCA1 are modulated by associated proteins, a yeast two-hybrid library was screened with the C-terminal 120 amino acids of ABCA1. Two PDZ proteins, α1-syntroplun and Lin7, were found to interact with ABCA1. Our -study suggested that α1-syntrophin is involved in intracellular signaling, which determines the stability of ABCA1, and modulates cellular cholesterol release.
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