Regulation of microtubule dynamics by suppression of microtubule assembly kinetics

TPX2 is a widely conserved microtubule‐associated protein that is required for mitotic spindle formation and function. In this study, we explored a potential role of TPX2 in regulating microtubule assembly kinetics, which could lead to downstream consequences for its effects on the parameters of microtubule dynamic instability. We found that TPX2 acts to suppress tubulin subunit off‐rates during microtubule assembly and disassembly. This allowed for the support of unprecedentedly slow rates of plus‐end microtubule growth, and to a dramatically reduced microtubule shortening rate. These changes in microtubule dynamics could be explained in computational simulations by a moderate increase in tubulin‐tubulin bond strength upon TPX2 association with the microtubule lattice, which in turn acts to reduce the departure rate of tubulin subunits from the microtubule ends. Further, our simulations naturally reproduced the suppression of catastrophe events in TPX2 as a direct result of the suppressed tubulin subunit off‐rates, likely due to increased retention of GTP‐tubulin subunits at the microtubule tip, which would lead to a larger GTP‐cap size. Thus, the direct suppression of tubulin subunit off‐rates by TPX2 during microtubule growth and shortening could provide a molecular mechanism to explain downstream changes in the parameters of microtubule dynamic instability in the presence of TPX2. Support or Funding Information NIGMS, National Institutes of Health