Structure and Function of the Circumsporozoite Protein

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DESCRIPTION (provided by the applicant): The circumsporozoite protein (CS) is the major surface protein of Plasmodium sporozoites. It is required for sporozoite development in the mosquito and functions in sporozoite adhesion to target cells. Despite its importance in the life of the parasite little is known about its structure. We now have data demonstrating that the CS is proteolytically processed. Cleavage is triggered by contact with cells and appears to be required for cell invasion. It is also not known how CS is anchored to the sporozoite plasma membrane. We have preliminary data suggesting that CS is lipid modified, however, we do not yet know if this lipid is part of a glycosyl phosphatidylinositol (GPI) anchor. The goal of this proposal is to continue our work on the post-translation modifications of this important protein and to elucidate the function of these modifications in the life of the parasite. The specific aims of this proposal are: 1) To determine the precise proteolytic cleavage site in CS and how the protein is anchored to the sporozoite plasma membrane. 2) To pursue functional studies of CS cleavage by; a) determining how cell contact triggers CS cleavage; b) whether CS cleavage is important in the mosquito; c) generating sporozoites with mutations in the CS cleavage site. 3) To characterize the cysteine proteases expressed in sporozoites and identify the CS protease. The work we propose is of relevance to the development of new drug therapies for malaria. Protease inhibitors are now used in many clinical settings and this work may lead to their use in the treatment of malaria.