Scavenger receptors (SR) are cell surface proteins that bind chemically modified lipoproteins and exhibit broad ligand binding specificities. We have identified three classes of vertebrate and invertebrate SRs: class A (SR-A), class B (SR-B) and class C (SR-C). They participate in or influence lipoprotein metabolism, development, host defense (innate immunity, protection against septic shock and viral infection), possibly asbestosis, recognition and clearance of damaged (apoptotic) cells and macromolecules, red blood cell maturation, female fertility and atherosclerosis/coronary heart disease (CHD). Many of their functions are directly related to health and disease and are consequences of their broad ligand binding specificities. One of these, SR-BI, is a physiologically relevant HDL receptor that controls the levels and fates of plasma HDL cholesterol, including delivery to the liver and steroidogenic tissues. SR-BI mediates selective uptake of HDL cholesterol, a poorly understood mechanism distinct from classic lipoprotein endocytic uptake and cholesterol effiux. The overall goals of this proposal are 1) to elucidate the biochemical and structural bases for the high affinity, broad ligand binding specificities of these receptors by determining how their ligand binding domains (e.g., collagenous and alpha-helical coiled-coil domains of SR-AI/II) recognize diverse arrays of structurally distinct ligands, 2) to provide additional insights into the novel molecular mechanism underlying selective lipid uptake and cholesterol efflux, and 3) to provide both experimental tools and a biochemical framework with which to assess further the functions of these unusual receptors. The work will rely on the generation and functional analysis of mutant receptors generated using standard and novel methods. Detailed characterization of the structures and distinctive binding properties of mammalian and invertebrate scavenger receptors will provide important tools for the analysis of scavenger receptor function and will probably suggest new approaches for the treatment and prevention of at least some of the related diseases (e.g., atherosclerosis, infectious disease, female infertility). The proposed work may lead to methods for predicting which physiologically relevant molecules are receptor ligands; this would provide additional avenues for exploring receptor function and, possibly, the design of pharmacologic reagents. In addition, clarification of the molecular bases of the broad bind specificities of scavenger receptors may provide insight into other biological systems in which broad binding specificity is important, e.g., multidrug resistance. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052212-13
Application #
7062454
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
1994-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
13
Fiscal Year
2006
Total Cost
$446,532
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Dockendorff, Chris; Faloon, Patrick W; Germain, Andrew et al. (2015) Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 25:2594-8
Dockendorff, Chris; Faloon, Patrick W; Pu, Jun et al. (2015) Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 25:2100-5
Tsukamoto, Kosuke; Wales, Thomas E; Daniels, Kathleen et al. (2013) Noncanonical role of the PDZ4 domain of the adaptor protein PDZK1 in the regulation of the hepatic high density lipoprotein receptor scavenger receptor class B, type I (SR-BI). J Biol Chem 288:19845-60
Tsukamoto, Kosuke; Mani, D R; Shi, Jianru et al. (2013) Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease. Proc Natl Acad Sci U S A 110:17023-8
Tsukamoto, Kosuke; Buck, Lorenna; Inman, Walker et al. (2013) Challenges in using cultured primary rodent hepatocytes or cell lines to study hepatic HDL receptor SR-BI regulation by its cytoplasmic adaptor PDZK1. PLoS One 8:e69725
Yu, Miao; Lau, Thomas Y; Carr, Steven A et al. (2012) Contributions of a disulfide bond and a reduced cysteine side chain to the intrinsic activity of the high-density lipoprotein receptor SR-BI. Biochemistry 51:10044-55
Brill, Alexander; Yesilaltay, Ayce; De Meyer, Simon F et al. (2012) Extrahepatic high-density lipoprotein receptor SR-BI and apoA-I protect against deep vein thrombosis in mice. Arterioscler Thromb Vasc Biol 32:1841-7
Gaidukov, Leonid; Nager, Andrew R; Xu, Shangzhe et al. (2011) Glycine dimerization motif in the N-terminal transmembrane domain of the high density lipoprotein receptor SR-BI required for normal receptor oligomerization and lipid transport. J Biol Chem 286:18452-64
Nieland, Thomas J F; Xu, Shangzhe; Penman, Marsha et al. (2011) Negatively cooperative binding of high-density lipoprotein to the HDL receptor SR-BI. Biochemistry 50:1818-30
Kocher, Olivier; Birrane, Gabriel; Yesilaltay, Ayce et al. (2011) Identification of the PDZ3 domain of the adaptor protein PDZK1 as a second, physiologically functional binding site for the C terminus of the high density lipoprotein receptor scavenger receptor class B type I. J Biol Chem 286:25171-86

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