Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco CA.
J Cell Biol. 2021 May 3;220(5). doi: 10.1083/jcb.202012079.
Microtubules are dynamic polymers that play fundamental roles in all eukaryotes. Despite their importance, how new microtubules form is poorly understood. Textbooks have focused on variations of a nucleation-elongation mechanism in which monomers rapidly equilibrate with an unstable oligomer (nucleus) that limits the rate of polymer formation; once formed, the polymer then elongates efficiently from this nucleus by monomer addition. Such models faithfully describe actin assembly, but they fail to account for how more complex polymers like hollow microtubules assemble. Here, we articulate a new model for microtubule formation that has three key features: (1) microtubules initiate via rectangular, sheet-like structures that grow faster the larger they become; (2) the dominant pathway proceeds via accretion, the stepwise addition of longitudinal or lateral layers; and (3) a "straightening penalty" to account for the energetic cost of tubulin's curved-to-straight conformational transition. This model can quantitatively fit experimental assembly data, providing new insights into biochemical determinants and assembly pathways for microtubule nucleation.
微管是一种动态聚合物，在所有真核生物中都发挥着基本作用。尽管它们很重要，但新的微管是如何形成的还知之甚少。教科书主要集中在核-延伸机制的变化上，其中单体迅速与不稳定的低聚物（核）达到平衡，核限制了聚合物形成的速度；一旦形成，聚合物就可以通过单体的添加有效地从这个核延伸。这种模型忠实地描述了肌动蛋白的组装，但它不能解释像中空微管这样更复杂的聚合物是如何组装的。在这里，我们提出了一个新的微管形成模型，该模型有三个关键特征：（1）微管通过长方形、片状结构起始，这些结构随着尺寸的增加而生长得更快；（2）主要途径是通过 accretion（逐步添加纵向或横向层）进行；（3）为了考虑微管蛋白弯曲到直线构象转变的能量成本，引入“变直惩罚”。该模型可以对实验组装数据进行定量拟合，为微管成核的生化决定因素和组装途径提供了新的见解。
