title: Molecular modeling and structure-based thermodynamic analysis of the StAR protein.
abstract: Although much progress has been achieved in the study of the steroidogenic acute regulatory protein (StAR) dependent cholesterol transfer inside mitochondria, not one mechanism can account for all experimental data obtained to date. We have thus investigated the possibility that molecular modeling and structure-based thermodynamic calculations (STC) could enlighten these discrepancies. Starting from the crystallographic data of the human MLN64, a StAR homology model was generated and subjected to STC to verify the importance of StAR structural alterations for proper function. As expected, the model resembled the MLN64 crystal, although no binding site "tunnel" was obtained. Instead, a closed cavity was discovered, approximately the size and shape of cholesterol. This suggests that StAR does indeed require structural alterations to allow cholesterol binding, most evidently by the C-terminal alpha-helix above the U-shaped beta-barrel. Through STC, it is shown that unfolding of this helix is probable and leads to a 2% subpopulation of partially unfolded StAR, supportive of both the intermembrane shuttle and the molten globule hypotheses.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Axel P
authors.initials: AP
authors.lastname: Mathieu
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: LeHoux
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003461:Crystallography; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C105684:STARD3 protein, human; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol