Sen Aritra, Kunwar Ambarish
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India.
Phys Biol. 2023 Apr 3;20(3). doi: 10.1088/1478-3975/acc301.
Microtubule (MT) severing enzymes Katanin and Spastin cut the MT into smaller fragments and are being studied extensively usingexperiments due to their crucial role in different cancers and neurodevelopmental disorders. It has been reported that the severing enzymes are either involved in increasing or decreasing the tubulin mass. Currently, there are a few analytical and computational models for MT amplification and severing. However, these models do not capture the action of MT severing explicitly, as these are based on partial differential equations in one dimension. On the other hand, a few discrete lattice-based models were used earlier to understand the activity of severing enzymes only on stabilized MTs. Hence, in this study, discrete lattice-based Monte Carlo models that included MT dynamics and severing enzyme activity have been developed to understand the effect of severing enzymes on tubulin mass, MT number, and MT length. It was found that the action of severing enzyme reduces average MT length while increasing their number; however, the total tubulin mass can decrease or increase depending on the concentration of GMPCPP (Guanylyl-(,)-methylene-diphosphonate)-which is a slowly hydrolyzable analogue of GTP (Guanosine triphosphate). Further, relative tubulin mass also depends on the detachment ratio of GTP/GMPCPP and Guanosine diphosphate tubulin dimers and the binding energies of tubulin dimers covered by the severing enzyme.
微管（MT）切断酶katanin和spastin可将微管切割成更小的片段，由于它们在不同癌症和神经发育障碍中发挥关键作用，因此正在通过实验进行广泛研究。据报道，这些切断酶要么参与增加要么减少微管蛋白质量。目前，有一些用于微管扩增和切断的分析和计算模型。然而，这些模型并未明确捕捉微管切断的作用，因为它们基于一维偏微分方程。另一方面，早期曾使用一些基于离散晶格的模型来仅了解切断酶对稳定微管的活性。因此，在本研究中，已开发出包含微管动力学和切断酶活性的基于离散晶格的蒙特卡罗模型，以了解切断酶对微管蛋白质量、微管数量和微管长度的影响。研究发现，切断酶的作用会缩短微管的平均长度，同时增加其数量；然而，微管蛋白的总质量可能会减少或增加，这取决于GMPCPP（鸟苷-（，）-亚甲基二磷酸）的浓度，GMPCPP是GTP（鸟苷三磷酸）的一种缓慢水解类似物。此外，相对微管蛋白质量还取决于GTP/GMPCPP与鸟苷二磷酸微管蛋白二聚体的解离率以及切断酶覆盖的微管蛋白二聚体的结合能。
