NMR Structure of the C-Terminal Transmembrane Domain of the HDL Receptor, SR-BI, and a Functionally Relevant Leucine Zipper Motif.
The interaction of high-density lipoprotein (HDL) with its receptor, scavenger receptor BI (SR-BI), is critical for lowering plasma cholesterol levels and reducing the risk for cardiovascular disease. The HDL/SR-BI complex facilitates delivery of cholesterol into cells and is likely mediated by receptor dimerization. This work describes the use of nuclear magnetic resonance (NMR) spectroscopy to generate the first high-resolution structure of the C-terminal transmembrane domain of SR-BI. This region of SR-BI harbors a leucine zipper dimerization motif, which when mutated impairs the ability of the receptor to bind HDL and mediate cholesterol delivery. These losses in function correlate with the inability of SR-BI to form dimers. We also identify juxtamembrane regions of the extracellular domain of SR-BI that may interact with the lipid surface to facilitate cholesterol transport functions of the receptor.
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Alexandra C
AC
Chadwick
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Davin R
DR
Jensen
Division of Endocrinology, Metabolism & Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Paul J
PJ
Hanson
Division of Endocrinology, Metabolism & Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Philip T
PT
Lange
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Sarah C
SC
Proudfoot
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Francis C
FC
Peterson
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: bvolkman@mcw.edu.
Brian F
BF
Volkman
Division of Endocrinology, Metabolism & Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: dsahoo@mcw.edu.
Daisy
D
Sahoo
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D016350:Leucine Zippers; D008075:Lipoproteins, HDL / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D051122:Scavenger Receptors, Class B / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D008075:Lipoproteins, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B
NMR; SR-BI; cholesterol; detergent micelle; dimerization; high density lipoprotein; juxtamembrane; leucine zipper; selective uptake; transmembrane domain