Structure and Function of the Circumsporozoite Protein

环子孢子蛋白的结构和功能

• 批准号: 7185118
• 负责人: Photini Sinnis
• 金额: $ 46.56万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185118
• 关键词: Structure; Function; Circumsporozoite; Protein

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.

描述(申请人提供)：环子孢子蛋白(CS)是疟原虫子孢子的主要表面蛋白。它是蚊子孢子发育所必需的，也是子孢子与靶细胞黏附所必需的。尽管它在寄生虫的生活中很重要，但人们对它的结构知之甚少。我们现在有数据表明CS是经过蛋白质降解处理的。卵裂是由与细胞接触触发的，似乎是细胞入侵所必需的。CS是如何固定在子孢子质膜上的也是未知的。我们有初步数据表明CS是脂类修饰的，然而，我们还不知道这种脂类是否是糖基磷脂酰肌醇(GPI)锚的一部分。这项建议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。 这一建议的具体目的是：1)确定CS中蛋白水解酶的准确切割位置，以及蛋白质如何锚定到子孢子质膜上。2)开展CS裂解的功能研究：a)确定细胞接触如何触发CS裂解；b)CS裂解对蚊子是否重要；c)产生CS裂解位点突变的子孢子。3)鉴定在子孢子中表达的半胱氨酸蛋白酶，并对半胱氨酸蛋白酶进行鉴定。 我们提议的工作与疟疾新药疗法的开发有关。现在许多临床环境中都使用了蛋白水解酶抑制剂，这项工作可能导致将其用于治疗疟疾。