SR-BI/CD36 Chimeric Receptors Define Extracellular Subdomains of SR-BI Critical for Cholesterol Transport

详细信息    查看全文

• 作者：Gabriella A. Kartz ; Rebecca L. Holme ; Kay Nicholson ; Daisy Sahoo
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：October 7, 2014
• 年：2014
• 卷：53
• 期：39
• 页码：6173-6182
• 全文大小：534K
• ISSN：1520-4995

文摘

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鈥檚 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鈥搇igand interactions and the various cholesterol transport functions of SR-BI.