title: StAR-related lipid transfer domain protein 5 binds primary bile acids.
abstract: Steroidogenic acute regulatory-related lipid transfer (START) domain proteins are involved in the nonvesicular intracellular transport of lipids and sterols. The STARD1 (STARD1 and STARD3) and STARD4 subfamilies (STARD4-6) have an internal cavity large enough to accommodate sterols. To provide a deeper understanding on the structural biology of this domain, the binding of sterols to STARD5, a member of the STARD4 subfamily, was monitored. The SAR by NMR [(1)H-(15)N heteronuclear single-quantum coherence (HSQC)] approach, complemented by circular dichroism (CD) and isothermal titration calorimetry (ITC), was used. Titration of STARD5 with cholic (CA) and chenodeoxycholic acid (CDCA), ligands of the farnesoid X receptor (FXR), leads to drastic perturbation of the (1)H-(15)N HSQC spectra and the identification of the residues in contact with those ligands. The most perturbed residues in presence of ligands are lining the internal cavity of the protein. Ka values of 1.8·10-(4) M(-1) and 6.3·10(4) M(-1) were measured for CA and CDCA, respectively. This is the first report of a START domain protein in complex with a sterol ligand. Our original findings indicate that STARD5 may be involved in the transport of bile acids rather than cholesterol.
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de lsanté, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Danny
authors.initials: D
authors.lastname: Létourneau
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lorin
authors.forename: Andrée
authors.initials: A
authors.lastname: Lefebvre
authors.forename: Vincent
authors.initials: V
authors.lastname: Frappier
authors.forename: Francis
authors.initials: F
authors.lastname: Gaudreault
authors.forename: Rafael
authors.initials: R
authors.lastname: Najmanovich
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: LeHoux
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D002635:Chenodeoxycholic Acid / Q000737:chemistry*; D019826:Cholic Acid / Q000737:chemistry*; D003001:Cloning, Molecular; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000592:standards; D008958:Models, Molecular; D055550:Protein Stability; D012015:Reference Standards; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D008024:Ligands; C456546:STARD5 protein, human; D002635:Chenodeoxycholic Acid; D019826:Cholic Acid