title: Thermodynamic and solution state NMR characterization of the binding of secondary and conjugated bile acids to STARD5.
abstract: STARD5 is a member of the STARD4 sub-family of START domain containing proteins specialized in the non-vesicular transport of lipids and sterols. We recently reported that STARD5 binds primary bile acids. Herein, we report on the biophysical and structural characterization of the binding of secondary and conjugated bile acids by STARD5 at physiological concentrations. We found that the absence of the 7α-OH group and its epimerization increase the affinity of secondary bile acids for STARD5. According to NMR titration and molecular modeling, the affinity depends mainly on the number and positions of the steroid ring hydroxyl groups and to a lesser extent on the presence or type of bile acid side-chain conjugation. Primary and secondary bile acids have different binding modes and display different positioning within the STARD5 binding pocket. The relative STARD5 affinity for the different bile acids studied is: DCA>LCA>CDCA>GDCA>TDCA>CA>UDCA. TCA and GCA do not bind significantly to STARD5. The impact of the ligand chemical structure on the thermodynamics of binding is discussed. The discovery of these new ligands suggests that STARD5 is involved in the cellular response elicited by bile acids and offers many entry points to decipher its physiological role.
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Létourneau
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lorin
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Andrée
authors.initials: A
authors.lastname: Lefebvre
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cabana
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.affiliation: Département de Biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada. Electronic address: Jean-Guy.LeHoux@USherbrooke.ca.
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: LeHoux
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D001647:Bile Acids and Salts / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001647:Bile Acids and Salts; D002352:Carrier Proteins; C456546:STARD5 protein, human
keywords: Bile acid; CA; CD; CDCA; CSD; Cholesterol metabolism; Circular dichroism; DCA; GCA; GDCA; HSQC; Heteronuclear Single Quantum Coherence; ITC; Isothermal titration calorimetry; LCA; NMR; NMR spectroscopy; Steroidogenic acute regulatory protein (StAR); TCA; TDCA; UDCA; chemical shift displacement; chenodeoxycholic acid; cholic acid; circular dichroism; deoxycholic acid; glycocholic acid; glycodeoxycholic acid; isothermal titration calorimetry; lithocholic acid; nuclear magnetic resonance; taurocholic acid; taurodeoxycholic acid; ursodeoxycholic acid