Structure and Function of the Circumsporozoite Protein

描述（由申请方提供）：环子孢子蛋白（CS）是疟原虫子孢子的主要表面蛋白。它是蚊子子孢子发育所必需的，并在子孢子粘附到靶细胞中起作用。尽管它在寄生虫的生活中很重要，但对其结构知之甚少。我们现在有数据表明CS是蛋白水解加工的。切割是由与细胞接触触发的，并且似乎是细胞侵入所必需的。也不知道CS是如何锚定在子孢子质膜上的。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）锚的一部分。该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活中的功能。 本研究的具体目的是：1）确定CS中蛋白质的精确裂解位点以及蛋白质如何锚定在子孢子质膜上。2)通过以下方式进行CS切割的功能研究：a）确定细胞接触如何触发CS切割; B）CS切割在蚊子中是否重要; c）产生CS切割位点突变的子孢子。3)目的研究子孢子中表达的半胱氨酸蛋白酶，并对CS蛋白酶进行鉴定。 我们提出的工作与疟疾新药物疗法的开发有关。蛋白酶抑制剂现在被用于许多临床环境，这项工作可能会导致他们在治疗疟疾的使用。

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.