Chadwick Alexandra C, Jensen Davin R, Hanson Paul J, Lange Philip T, Proudfoot Sarah C, Peterson Francis C, Volkman Brian F, Sahoo Daisy
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Division of Endocrinology, Metabolism & Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Structure. 2017 Mar 7;25(3):446-457. doi: 10.1016/j.str.2017.01.001. Epub 2017 Feb 2.
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.
高密度脂蛋白（HDL）与其受体清道夫受体BI（SR-BI）的相互作用对于降低血浆胆固醇水平和降低心血管疾病风险至关重要。HDL/SR-BI复合物促进胆固醇向细胞内的转运，这可能是由受体二聚化介导的。这项工作描述了利用核磁共振（NMR）光谱法生成SR-BI C端跨膜结构域的首个高分辨率结构。SR-BI的这一区域含有一个亮氨酸拉链二聚化基序，该基序发生突变时会损害受体结合HDL并介导胆固醇转运的能力。这些功能丧失与SR-BI无法形成二聚体相关。我们还确定了SR-BI细胞外结构域的近膜区域，该区域可能与脂质表面相互作用，以促进受体的胆固醇转运功能。
