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首页> 外文期刊>Biochemistry >SR-BI/CD36 Chimeric Receptors Define Extracellular Subdomains of SR-BI Critical for Cholesterol Transport
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SR-BI/CD36 Chimeric Receptors Define Extracellular Subdomains of SR-BI Critical for Cholesterol Transport

机译：SR-BI / CD36嵌合受体定义了胆固醇转运至关重要的SR-BI的胞外亚结构域

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摘要

High-density lipoproteins (HDLs) are athero-protective, primarily because of their ability to promote cholesterol flux from peripheral tissues to the liver by reverse cholesterol transport (RCT). The delivery of HDL-cholesteryl esters (CE) into cells is mediated by the HDL receptor, scavenger receptor class B type I (SR-BI), a promising target for enhancing whole body cholesterol disposal and preventing cardiovascular disease. A detailed understanding of the structural determinants underlying proper SR-BI/HDL alignment that supports the selective uptake of HDL-CE into cells remains lacking. To this end, we exploited CD36, a class B scavenger receptor with a predicted topology similar to that of SR-BI that binds HDL but is unable to mediate efficient selective uptake of HDL-CE. We generated a series of SR-BI/CD36 chimeric receptors that span the extracellular (EC) domain of SR-BI to delineate regions that are essential for SR-BI's cholesterol transport functions. All 16 SR-BI/CD36 chimeras were transiently expressed in COS-7 cells, and their plasma membrane localization was confirmed. The majority of SR-BI/CD36 chimeric receptors displayed significant reductions in their ability to (i) bind HDL, (ii) deliver HDL-CE to cells, (iii) mediate efflux of free cholesterol (FC) to HDL, and (iv) redistribute plasma membrane domains of FC. We also demonstrated that changes in SR-BI function were independent of receptor oligomerization. Altogether, we have identified discrete subdomains, particularly in the N-terminal and C-terminal regions of the EC domain of SR-BI, that are critical for productive receptor-ligand interactions and the various cholesterol transport functions of SR-BI.
机译：高密度脂蛋白（HDL）具有动脉粥样硬化保护作用，这主要是因为它们能够通过逆向胆固醇转运（RCT）促进胆固醇从周围组织向肝脏的流动。 HDL胆固醇酯（CE）向细胞的传递是由HDL受体，B类I型清除剂受体（SR-BI）介导的，该受体是增强全身胆固醇处置和预防心血管疾病的有希望的目标。底层适当SR-BI / HDL对准支持HDL-CE的选择性摄取到细胞遗体缺少结构性决定的详细理解。为此，我们开发了CD36，一种B类清道夫受体，其预测拓扑类似于与HDL结合但无法介导HDL-CE选择性吸收的SR-BI拓扑。我们生成了一系列SR-BI / CD36嵌合受体，它们跨越SR-BI的胞外（EC）域，以描绘出SR-BI胆固醇转运功能必不可少的区域。所有16个SR-BI / CD36嵌合体均在COS-7细胞中瞬时表达，并确认了它们的质膜定位。大多数SR-BI / CD36嵌合受体在其（i）结合HDL，（ii）将HDL-CE传递至细胞，（iii）介导游离胆固醇（FC）向HDL的流出以及（iv ）重新分布FC的质膜区域。我们还证明了SR-BI功能的变化与受体低聚无关。总而言之，我们已经确定了离散的亚结构域，特别是在SR-BI的EC域的N端和C端区域，这对于生产性受体-配体相互作用和SR-BI的各种胆固醇转运功能至关重要。

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