Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 200241, Shanghai, China.
iHuman Institute, ShanghaiTech University, 201210, Shanghai, China.
Commun Biol. 2023 Aug 31;6(1):895. doi: 10.1038/s42003-023-05277-0.
Microneme protein 2 (MIC2) and MIC2-associated protein (M2AP) play crucial roles in the gliding motility and host cell invasion of Toxoplasma gondii. Complex formation between MIC2 and M2AP is required for maturation and transport from the microneme to the parasite surface. Previous studies showed that M2AP associates with the 6 TSR domain of MIC2 (TSR6), but the detailed interaction remains unclear. In this study, we report crystal structures of M2AP alone and in complex with TSR6. TSR domains have an unusually thin, long structure with a layer of intercalated residues on one side. The non-layered side of TSR6 with hotspot residue His-620 at the center binds to M2AP. Remarkably, we show that TSR6 residue Y602 is dynamic; it equilibrates between being part of the layer (the layered state) and in a flipped-out state in the absence of M2AP. However, when bound to M2AP, Y602 shifts to the flipped-out state. Our findings provide insights into the association and stabilization of MIC2-M2AP complex, and may be used to develop new therapies to prevent infections caused by this parasite.
微线体蛋白 2（MIC2）和 MIC2 相关蛋白（M2AP）在刚地弓形虫的滑行运动和宿主细胞入侵中发挥着关键作用。MIC2 和 M2AP 之间的复合物形成对于从微线体向寄生虫表面的成熟和运输是必需的。先前的研究表明，M2AP 与 MIC2 的 6 个 TSR 结构域（TSR6）相关联，但详细的相互作用仍不清楚。在这项研究中，我们报告了 M2AP 单独和与 TSR6 复合物的晶体结构。TSR 结构域具有异常薄而长的结构，一侧有一层插入的残基。中心具有热点残基 His-620 的非层状 TSR6 侧与 M2AP 结合。值得注意的是，我们表明 TSR6 残基 Y602 是动态的；在没有 M2AP 的情况下，它在层（层状状态）和翻转状态之间平衡。然而，当与 M2AP 结合时，Y602 转变为翻转状态。我们的发现提供了对 MIC2-M2AP 复合物的关联和稳定的深入了解，并且可能用于开发新的疗法来预防这种寄生虫引起的感染。
