整合动态结构生物学揭示大GTP酶寡聚化所必需的关键构象体
Integrative dynamic structural biology unveils conformers essential for the oligomerization of a large GTPase
AI总结：
该研究利用整合动态结构生物学技术解析了人源GBP1从纳秒到毫秒的构象动力学，发现C末端效应域的GTP非依赖性柔性及关键构象体，揭示了其可逆寡聚化的功能设计原则。
摘要：
鸟苷酸结合蛋白（GBPs）是可溶性动力素样蛋白，具有结构化结构域，可发生构象转变以实现GTP调控的寡聚化，从而作为哺乳动物细胞先天免疫系统的一部分发挥功能——通过破坏膜结构攻击胞内寄生虫。该过程的结构基础和机制尚不清楚。因此，我们应用中子自旋回波、X射线散射、荧光和EPR光谱作为整合动态结构生物学技术，研究人源GBP1（hGBP1）。我们通过亚结构域的运动谱，绘制了hGBP1从纳秒到毫秒尺度的基本动力学图谱。我们发现C末端效应结构域在微秒时间尺度上具有不依赖GTP的柔性，并在结构上表征了关键构象体，这些构象体对于hGBP1能够像折叠刀一样打开以进行寡聚化至关重要。这揭示了内在柔性、GTP触发的GTPase结构域结合以及组装依赖的GTP水解作为hGBP1的功能设计原则，控制其在极性组装体中的可逆寡聚化及随后凝聚体的形成。
英文摘要：
Guanylate binding proteins (GBPs) are soluble dynamin-like proteins with structured domains that undergo a conformational transition for GTP-controlled oligomerization to exert their function as part of the innate immune system of mammalian cells - attacking intra-cellular parasites by disrupting their membranes. The structural basis and mechanism of this process is unknown. Therefore, we apply neutron spin echo, X-ray scattering, fluorescence, and EPR spectroscopy as techniques for integrative dynamic structural biology to human GBP1 (hGBP1). We mapped hGBP1's essential dynamics from nanoseconds to milliseconds by motional spectra of sub-domains. We find a GTP-independent flexibility of the C-terminal effector domain in the $μ$s-regime and structurally characterize conformers being essential that hGBP1 can open like a pocketknife for oligomerization. This unveils the intrinsic flexibility, a GTP-triggered association of the GTPase-domains and assembly-dependent GTP-hydrolysis as functional design principles of hGBP1 that control its reversible oligomerization in polar assemblies and the subsequent formation of condensates.
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