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. ? ?
Showing the most recent 10 out of 57 publications
