Connelly M A, Klein S M, Azhar S, Abumrad N A, Williams D L
Department of Pharmacological Sciences, University Medical Center, State University at Stony Brook, Stony Brook, New York, 11794-8651, USA.
J Biol Chem. 1999 Jan 1;274(1):41-7. doi: 10.1074/jbc.274.1.41.
Scavenger receptor BI (SR-BI) mediates the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without internalization and degradation of the HDL particle. The biochemical mechanism by which SR-BI mediates the selective uptake of HDL CE is poorly understood. Given that CE transfer will occur to some extent from HDL to protein-free synthetic membranes, one hypothesis is that the role of SR-BI is primarily to tether HDL close to the cell surface to facilitate CE transfer from the particle to the plasma membrane. In the present study, this hypothesis was tested by comparing the selective uptake of HDL CE mediated by mouse SR-BI (mSR-BI) with that mediated by rat CD36 (rCD36), a closely related class B scavenger receptor. Both mSR-BI and rCD36 bind HDL with high affinity, and both receptors mediate HDL CE selective uptake. However, SR-BI mediates selective uptake of HDL CE with a 7-fold greater efficiency than rCD36. HDL CE selective uptake mediated by rCD36 is dependent on HDL binding to the receptor, since a mutation that blocks HDL binding also blocks HDL CE selective uptake. These data lead us to hypothesize that one component of HDL CE selective uptake is the tethering of HDL particles to the cell surface. To explore the molecular domains responsible for the greater efficiency of selective uptake by mSR-BI, we compared binding and selective uptake among mSR-BI, scavenger receptor BII, and various chimeric receptors formed from mSR-BI and rCD36. The results show that the extracellular domain of mSR-BI is essential for efficient HDL CE uptake, but the C-terminal cytoplasmic tail also has a major influence on the selective uptake process.
清道夫受体BI（SR-BI）介导高密度脂蛋白（HDL）胆固醇酯（CE）的选择性摄取，在这个过程中，HDL CE被摄入细胞，而HDL颗粒不发生内化和降解。SR-BI介导HDL CE选择性摄取的生化机制目前还知之甚少。鉴于CE会在一定程度上从HDL转移至无蛋白的合成膜，一种假说认为，SR-BI的作用主要是将HDL固定在细胞表面附近，以促进CE从颗粒转移至质膜。在本研究中，通过比较小鼠SR-BI（mSR-BI）介导的HDL CE选择性摄取与大鼠CD36（rCD36，一种密切相关的B类清道夫受体）介导的HDL CE选择性摄取，对这一假说进行了验证。mSR-BI和rCD36都以高亲和力结合HDL，且两种受体都介导HDL CE的选择性摄取。然而，SR-BI介导HDL CE选择性摄取的效率比rCD36高7倍。rCD36介导的HDL CE选择性摄取依赖于HDL与受体的结合，因为阻断HDL结合的突变也会阻断HDL CE的选择性摄取。这些数据使我们推测，HDL CE选择性摄取的一个组成部分是HDL颗粒与细胞表面的固定。为了探究导致mSR-BI选择性摄取效率更高的分子结构域，我们比较了mSR-BI、清道夫受体BII以及由mSR-BI和rCD36形成的各种嵌合受体的结合和选择性摄取情况。结果表明，mSR-BI的胞外结构域对于高效摄取HDL CE至关重要，但C端胞质尾对选择性摄取过程也有重要影响。
