title: 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.
abstract: 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 degradation of the HDL particle. In addition, SR-BI stimulates the bi-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 from plasma HDL. SR-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanced 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 SR-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activities related to HDL CE selective uptake, bi-directional FC flux, and the alteration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI. The N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma membrane. The C-terminal tail of SR-BI is dispensable for activity as well for targeting to the plasma membrane. Thus, multiple distinct functional activities are localized to the SR-BI extracellular domain.
authors.affiliation: Department of Pharmacological Sciences, University Medical Center, State University of New York at Stony Brook, 11794-8651, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Connelly
authors.forename: M
authors.initials: M
authors.lastname: de la Llera-Moya
authors.forename: P
authors.initials: P
authors.lastname: Monzo
authors.forename: P G
authors.initials: PG
authors.lastname: Yancey
authors.forename: D
authors.initials: D
authors.lastname: Drazul
authors.forename: G
authors.initials: G
authors.lastname: Stoudt
authors.forename: N
authors.initials: N
authors.lastname: Fournier
authors.forename: S M
authors.initials: SM
authors.lastname: Klein
authors.forename: G H
authors.initials: GH
authors.lastname: Rothblat
authors.forename: D L
authors.initials: DL
authors.lastname: Williams
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D018955:CD36 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005110:Extracellular Space / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051122:Scavenger Receptors, Class B
chemical_list: D018955:CD36 Antigens; D002788:Cholesterol Esters; C059714:HDL cholesteryl ester; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011993:Recombinant Fusion Proteins; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D002784:Cholesterol