This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mosquitoes are a vector agent that carries disease-causing viruses and parasites from person to person without catching the disease themselves. Mosquitoes are estimated to transmit disease to more than 70 million people annually in Africa, South America, Central America, Mexico and much of Asia with millions of resulting deaths. In Europe, Russia, Greenland, Canada, the United States, Australia, New Zealand, the UK, Japan and other temperate and developed countries, mosquito bites are now mostly an irritating nuisance;but still cause some deaths each year. Insects have an absolute dietary need for cholesterol (a component of cell membranes and ecdysteroid biosynthesis) which they themselves cannot de novo synthesize. All insects, therefore, must be able to transport cholesterol into and around the cell cytoplasm as needed. This must include at least the ability to uptake cholesterol for the construction of cellular membranes, transport cholesterol to the peroxisome for catabolization and for storage/mobilization of cholesterol in the fat body. Therefore, cholesterol has to be trafficked someway between the cell membrane and the lipid droplet, which has been shown not to be carried out in insects by high-density lipid endocytosis or loading as in the vertebrates. Sterol carrier protein-2 (SCP-2) was first isolated as a cholesterol carrier protein in vertebrates. Recently, the genes for SCP-2 and SCP-X (AeSCP-X) from the yellow fever mosquito, Aedes aegypti (AeSCP-2) were isolated. The AeSCP-2 has a high degree of homology to the rat and human SCP-2.
Specific Aims :We propose a biophysical study to elucidate the molecular details in the structure/function relationship of the sterol carrier protein-2 from the yellow fever mosquito Aedes aegypti (AeSCP-2) and one of its target ligand: cholesterol. We will use NMR spectroscopy to determine the structure of apo-AeSCP-2 and cholesterol-bound complex of AeSCP-2 and monitor ligand and inhibitor binding to AeSCP-2.
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