微管动力学由成簇原纤维的构象和稳定性所定义。
Microtubule dynamics are defined by conformations and stability of clustered protofilaments.
作者信息
Kalutskii Maksim, Grubmüller Helmut, Volkov Vladimir A, Igaev Maxim
机构信息
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Göttingen D-37077, Germany.
Centre for Molecular Cell Biology, School of Biological and Behavioural Sciences, Queen Mary University of London, London E1 4NS, United Kingdom.
出版信息
Proc Natl Acad Sci U S A. 2025 Jun 3;122(22):e2424263122. doi: 10.1073/pnas.2424263122. Epub 2025 May 29.
Microtubules are dynamic cytoskeletal polymers that add and lose tubulin dimers at their ends. Microtubule growth, shortening, and transitions between them are linked to GTP hydrolysis. Recent evidence suggests that flexible tubulin protofilaments at microtubule ends adopt a variety of shapes, complicating structural analysis using conventional techniques. Therefore, the link between GTP hydrolysis, protofilament structure and microtubule polymerization state is poorly understood. Here, we investigate the conformational dynamics of microtubule ends using coarse-grained modeling supported by atomistic simulations and cryoelectron tomography. We show that individual bent protofilaments organize in clusters, transient precursors to the straight microtubule lattice, with GTP-bound ends showing elevated and more persistent cluster formation. Differences in the mechanical properties of GTP- and GDP-protofilaments result in differences in intracluster tension, determining both clustering propensity and protofilament length. We propose that conformational selection at microtubule ends favors long-lived clusters of short GTP-protofilaments that are more prone to forming a straight microtubule lattice and accommodating new tubulin dimers. Conversely, microtubule ends trapped in states with unevenly long and stiff GDP-protofilaments are more prone to shortening. We conclude that protofilament clustering is the key phenomenon that links the hydrolysis state of single tubulins to the polymerization state of the entire microtubule.
微管是动态的细胞骨架聚合物,在其末端添加和丢失微管蛋白二聚体。微管的生长、缩短以及它们之间的转变与GTP水解有关。最近的证据表明,微管末端的柔性微管蛋白原纤维呈现出多种形状,这使得使用传统技术进行结构分析变得复杂。因此,GTP水解、原纤维结构和微管聚合状态之间的联系尚不清楚。在这里,我们使用由原子模拟和冷冻电子断层扫描支持的粗粒度模型来研究微管末端的构象动力学。我们表明,单个弯曲的原纤维聚集在一起,形成直的微管晶格的瞬时前体,GTP结合的末端显示出更高且更持久的聚集形成。GTP和GDP原纤维的力学性质差异导致簇内张力的差异,从而决定了聚集倾向和原纤维长度。我们提出,微管末端的构象选择有利于短GTP原纤维的长寿命簇,这些簇更容易形成直的微管晶格并容纳新的微管蛋白二聚体。相反,被困在具有不均匀长且僵硬的GDP原纤维状态的微管末端更容易缩短。我们得出结论,原纤维聚集是将单个微管蛋白的水解状态与整个微管的聚合状态联系起来的关键现象。