Analysis of chimeric receptors shows that multiple distinct functional activities of scavenger receptor, class B, type I (SR-BI), are localized to the extracellular receptor domain

Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cholesteryl eater (CE), a process by which HDL CE is tak en into the cell without degradation of the HDL particle. In addition, SR-B I stimulates the hi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC f rom plasma HDL. S;R-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanc ed sensitivity of membrane cholesterol to extracellular cholesterol oxidase . In contrast, CD36, a closely related class B scavenger receptor, has none of these activities despite binding HDL with high affinity. In the present study, analyses of chimeric SB-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activiti es related to HDL CE selective uptake, bi-directional FC flux, and the alte ration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI, T he N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma me mbrane. The C-terminal tail of SR-BI is dispensable for activity as well fo r targeting to the plasma membrane. Thus, multiple distinct functional acti vities are localized to the SR-BI extracellular domain.