The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host.
The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host.
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DOI：
10.1084/jem.20101488
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发表时间：
2011-02-14
期刊：
影响因子：
--
通讯作者：
Sinnis P
中科院分区：
文献类型：
--
作者：
Coppi A;Natarajan R;Pradel G;Bennett BL;James ER;Roggero MA;Corradin G;Persson C;Tewari R;Sinnis P
构象变化影响疟原虫子孢子表面表达的环子孢子蛋白的功能特性。疟原虫子孢子从蚊子中肠到哺乳动物肝脏经历了一段非凡的旅程。子孢子的主要表面蛋白，环子孢子蛋白（CSP），是子孢子发育所需的多功能蛋白质，可能介导这一过程的几个步骤。在这项研究中，我们表明 CSP 有两种构象状态，一种是 C 端细胞粘附结构域暴露的粘附构象，另一种是 N 末端掩盖该结构域的非粘附构象。我们证明细胞粘附结构域在子孢子发育和肝细胞侵袭中发挥作用。在这两个事件之间，子孢子必须从蚊子中肠迁移到哺乳动物肝脏，并且细胞粘附结构域的 N 末端掩蔽使子孢子保持在迁移状态。在哺乳动物宿主中，CSP 的蛋白水解裂解调节向粘附构象的转换，高度保守的 I 区在此过程中发挥着关键作用。如果 CSP 结构域结构发生改变，使得细胞粘附结构域持续暴露，则大多数子孢子不会到达其靶器官，并且在哺乳动物宿主中，它们会直接从接种部位引发血液阶段感染。这些数据提供了与疟疾疫苗开发相关的结构-功能信息。
Conformational changes influence functional properties of circumsporozoite protein expressed on the surface of Plasmodium sporozoites. Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite’s major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure–function information relevant to malaria vaccine development.
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影响因子：
6.7
作者：
Ghosh, Anil K.;Devenport, Martin;Jethwaney, Deepa;Kalume, Dario E.;Pandey, Akhilesh;Anderson, Vernon E.;Sultan, Ali A.;Kumar, Nirbhay;Jacobs-Lorena, Marcelo
通讯作者：
Jacobs-Lorena, Marcelo
影响因子：
3.1
作者：
Medica, DL;Sinnis, P
通讯作者：
Sinnis, P
影响因子：
64.5
作者：
CERAMI, C;FREVERT, U;NUSSENZWEIG, V
通讯作者：
NUSSENZWEIG, V
影响因子：
64.8
作者：
Menard, R;Sultan, AA;Nussenzweig, V
通讯作者：
Nussenzweig, V
影响因子：
4.8
作者：
Pinzon-Ortiz, C;Friedman, J;Sinnis, P
通讯作者：
Sinnis, P