Paper detail

A theoretical model for attachment lifetimes of kinetochore-microtubules: Mechano-kinetic "catch-bond" mechanism for error-correction

Before cell division, two identical copies of chromosomes are pulled apart by microtubule (MT) filaments that approach the chromosomes from the opposite poles a mitotic spindle. Connection between the MTs and the chromosomes are mediated by a molecular complex called kinetochore. An externally applied tension can lead to detachment of the MTs from the kinetochore; the mean lifetime of such an attachment is essentially a mean first-passage time. In their in-vitro pioneering single-kinetochore experiments, Akiyoshi et al. (Nature 468, 576 (2010)), observed that the mean lifetimes of reconstituted MT-kinetochore attachments vary non-monotonically with increasing tension. The counter-intuitive stabilization of the attachments by small load forces was interpreted in terms of a catch-bond-like mechanism based on a phenomenological 2-state kinetic model. Here we develop the first detailed microscopic model for studying the dependence of the lifetime of the MT-kinetochore attachment on (a) the structure, (b) energetics, and (c) kinetics of the coupling. The catch-bond-like mechanism emerges naturally from this model. Moreover, in-silico experiments on this model reveal further interesting phenomena, arising from the subtle effects of competing sub-processes, which are likely to motivate new experiments in this emerging area of single-particle biophysics.