The selective uptake of cholesteryl ester (CE) from lipoprotein particles such as HDL is a process by which HDL core-CE is taken into cells without a parallel uptake and degradation of the HDL particle itself. It represents a major route for the delivery of CEs to steroid producing tissues of rodents and humans. Scavenger receptor, class B, type I (SR-BI), a member of the CD36 super-family of proteins, has been identified as an authentic HDL receptor that mediates-the uptake of HDL-CEs via this process, and immunochemical analyses indicate that it is expressed most abundantly in the steroidogenic cells and liver. Our published and preliminary data provide evidence that the physical state of the SR-BI protein and architectural changes in tissue induced by the expression of SR-BI .have major effects on the efficiency of the selective pathway. These data led us to suggest that the dimeric and higher order oligomeric forms of SR-BI are intimately involved in regulating SR-BI-mediated selective HDL-CE transport, and moreover, that these physical states of SR-BI contribute to the formation of cell surface (microvillar) channels to further enhance the efficiency of the selective pathway.
The specific aims of this proposal are: 1) to determine the contribution of SR-BI's C-terminal cytoplasmic domain in regulating SR-BI dimer formation; 2) to determine the contribution of the extracellular domain (ECD) of SR-BI either independently, or in cooperation with C- terminal domain, in regulating SR-BI dimerization and function; and 3) to determine whether SR-BI interacting accessory proteins (i.e., PDZ domain containing proteins and/or ERM family proteins in connection with the actin cytoskeleton) contribute to SR-BI dimer formation and/or play an essential role in SR-BI function. The hypothesis which drives this proposal is that dimer formation and concomitant surface architectural changes are necessary for efficient delivery of lipoprotein cholesteryl esters via the """"""""selective"""""""" uptake process. The experiments proposed will determine to what extent this is true, and at the same time, attempt to identify specific sites on both the SR-BI molecule and SR-BI interacting accessory proteins (PDZ, ERM, and actin proteins) which are involved in the dimerization process and in microvillar channel formation. ? ?
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