Implications of conformational flexibility, lipid binding, and regulatory domains in cell-traversal protein CelTOS for apicomplexan migration.
Implications of conformational flexibility, lipid binding, and regulatory domains in cell-traversal protein CelTOS for apicomplexan migration.
复制标题
DOI：
10.1016/j.jbc.2022.102241
复制
发表时间：
2022-09
影响因子：
4.8
通讯作者：
Tolia, Niraj H.
中科院分区：
文献类型：
--
作者：
Kumar, Hirdesh;Jimah, John R.;Misal, Santosh A.;Salinas, Nichole D.;Fried, Michal;Schlesinger, Paul H.;Tolia, Niraj H.
疟疾和其他由顶复门引起的疾病影响着数百万人、农业动物和宠物。细胞穿越是多种顶复门寄生虫通过宿主细胞迁移的共同特征，可以用于开发针对这些致命寄生虫的治疗方法。在这里，我们提供了深入的机制的细胞穿越蛋白的动合子和子孢子（CelTOS），一个保守的细胞穿越蛋白在顶复门寄生虫和疟疾疫苗候选人。CelTOS先前已被证明可以在细胞膜上形成孔，使寄生虫能够穿过细胞。我们建立了间日疟原虫CelTOS的不同蛋白质区域的作用，并研究孔形成的机制。我们进一步证明，CelTOS二聚体解离所需的孔形成，单体之间的二硫键桥抑制孔的形成，这种抑制被救出二硫键桥还原。我们还表明，螺旋不稳定的氨基酸，Pro127，允许CelTOS经历显着的构象变化组装成孔。CelTOS的柔性C末端是限制孔形成的负调节剂。最后，我们强调，脂质结合是孔组装的先决条件，因为CelTOS中的磷脂结合位点的突变导致脂质结合的丧失和废除孔的形成。这些发现确定了CelTOS中的关键区域，将有助于理解疟疾和其他顶复门寄生虫的出口机制，并对研究其他必要的成孔蛋白的功能具有意义。
Malaria and other apicomplexan-caused diseases affect millions of humans, agricultural animals, and pets. Cell traversal is a common feature used by multiple apicomplexan parasites to migrate through host cells and can be exploited to develop therapeutics against these deadly parasites. Here, we provide insights into the mechanism of the Cell-traversal protein for ookinetes and sporozoites (CelTOS), a conserved cell-traversal protein in apicomplexan parasites and malaria vaccine candidate. CelTOS has previously been shown to form pores in cell membranes to enable traversal of parasites through cells. We establish roles for the distinct protein regions of Plasmodium vivax CelTOS and examine the mechanism of pore formation. We further demonstrate that CelTOS dimer dissociation is required for pore formation, as disulfide bridging between monomers inhibits pore formation, and this inhibition is rescued by disulfide-bridge reduction. We also show that a helix-destabilizing amino acid, Pro127, allows CelTOS to undergo significant conformational changes to assemble into pores. The flexible C terminus of CelTOS is a negative regulator that limits pore formation. Finally, we highlight that lipid binding is a prerequisite for pore assembly as mutation of a phospholipids-binding site in CelTOS resulted in loss of lipid binding and abrogated pore formation. These findings identify critical regions in CelTOS and will aid in understanding the egress mechanism of malaria and other apicomplexan parasites as well as have implications for studying the function of other essential pore-forming proteins.
登录
查看更多内容
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
4.4
作者：
Kiss, Peter T.;Baranyai, Andras
通讯作者：
Baranyai, Andras
DOI：
10.1111/j.1550-7408.1980.tb04228.x
发表时间：
1980-01-01
期刊：
JOURNAL OF PROTOZOOLOGY
影响因子：
--
作者：
LEVINE, ND;CORLISS, JO;WALLACE, FG
通讯作者：
WALLACE, FG
影响因子：
3.7
作者：
Bergmann-Leitner, Elke S.;Mease, Ryan M.;Angov, Evelina
通讯作者：
Angov, Evelina
影响因子：
6.7
作者：
Kumar, Hirdesh;Tolia, Niraj H.
通讯作者：
Tolia, Niraj H.