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Computational model of kinetochore-microtubule attachments Bidone, Tamara


The ability of cells to separate chromosomes during mitosis is critical to several phases of their physiology. Chromosome segregation is mediated by spindle microtubules that attach to mitotic kinetochores via a dynamic protein interface, which includes Ndc80 and its accessory proteins, Ska, Cdt1 and ch-TOG [1-3]. The Ndc80 complex forms the core component of the attachment sites while Ska, Cdt1 and ch-TOG binds kinetochores via the Ndc80 complex. From prometaphase to metaphase, the kinetochore levels of Ska and Cdt1 increase in Hela cells, while that of Ndc80 remains constant. This suggests a correlation between concentration of proteins at the kinetochore-microtubule (kMT) interface and increasing amounts of load during mitosis. Interestingly, while being dynamic, the kMT interface ensures stability of the connection between chromosomes and kinetochore microtubules. How the various interface proteins interplay to ensure a dynamic yet stable connection is not known because their exact roles in this process are still elusive. An interesting hypothesis is that the Ndc80-accessory proteins Ska, Cdt1 and ch-TOG directly strengthen the kinetochore-microtubule interface by forming additional connections between kinetochore-bound Ndc80 and spindle microtubules. However, since Ska, Cdt1 and ch-TOG dynamically form and break their connections with microtubules, a synergy between them is likely to exist. Here, in order to characterize the synergy between Ska, Cdt1 and ch-TOG, we developed a new computational model, based on a kinetic Monte Carlo approach. The model allowed us to explicitly incorporate Ndc80, Ska1, Cdt1 and ch-TOG, isolate their contributions, and characterize their synergistic effects on the stability of the interface. Each protein is defined by a position along a tubulin protofilament, and exists in two states, bound or unbound, while undergoing biased diffusion, as observed in experiments. The model also incorporates tension-dependent unbinding rates for each protein, including catch bond kinetics for ch-TOG, as detected experimentally [2]. As for the output, the model evaluates: (i) displacement of the kMT interface along the tubulin protofilament; (ii) time of kMT attachment under tension; and (iii) kMT attachment rupture force, corresponding to the force that detaches all proteins. We find that combining Ndc80, Ska and Cdt1 enhances kMT attachment strength with respect to individual components. Ch-TOG further strengthens the complex because of its catch bond kinetics. In addition, the model shows that the rupture force, corresponding to the load under which no protein is bound, increases in proportion to the number of simulated microtubules. Taken together, our results provide important mechanistic insights into how kMT proteins coordinate with each other to withstand tension and ensure accurate chromosome segregation.

[1] D. Varma, and E. D. Salmon. J. Cell. Sci., 2013.
[2] M. P. Miller, C.L. Asbury, and S. Biggins. Cell, 2016.
[3] S. Agarwal, K.P. Smith, Y. Zhou, A. Suzuki, R.J. McKenney, and D. Varma. J. Cell Biol., 2018

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