Structure and Function of the Circumsporozoite Protein

描述（由申请人提供）：环孢子子蛋白（CS）是疟原虫孢子子的主要表面蛋白。它是蚊子孢子子发育所必需的，并在孢子子粘附靶细胞中起作用。尽管它在寄生虫的生命中很重要，但人们对它的结构知之甚少。我们现在有数据表明CS是被蛋白水解处理的。切割是通过与细胞接触而触发的，似乎是细胞入侵所必需的。也不知道CS是如何固定在孢子胞质膜上的。我们有初步的数据表明CS是脂质修饰的，然而，我们还不知道这种脂质是否是糖基磷脂酰肌醇（GPI）锚定的一部分。本提案的目标是继续我们对这一重要蛋白质的翻译后修饰的工作，并阐明这些修饰在寄生虫生命中的功能。

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.