Molecular mechanisms for microtubule length regulation by kinesin-8 and XMAP215 proteins.

Abstract

The cytoskeleton is regulated by a plethora of enzymes that influence the stability and dynamics of cytoskeletal filaments. How microtubules (MTs) are controlled is of particular importance for mitosis, during which dynamic MTs are responsible for proper segregation of chromosomes. Molecular motors of the kinesin-8 protein family have been shown to depolymerize MTs in a length-dependent manner, and recent experimental and theoretical evidence suggests a possible role for kinesin-8 in the dynamic regulation of MTs. However, so far the detailed molecular mechanisms of how these molecular motors interact with the growing MT tip remain elusive. Here we show that two distinct scenarios for the interactions of kinesin-8 with the MT tip lead to qualitatively different MT dynamics, including accurate length control as well as intermittent dynamics. We give a comprehensive analysis of the regimes where length regulation is possible and characterize how the stationary length depends on the biochemical rates and the bulk concentrations of the various proteins. For a neutral scenario, where MTs grow irrespective of whether the MT tip is occupied by a molecular motor, length regulation is possible only for a narrow range of biochemical rates, and, in particular, limited to small polymerization rates. By contrast, for an inhibition scenario, where the presence of a motor at the MT tip inhibits MT growth, the regime where length regulation is possible is extremely broad and includes high growth rates. These results also apply to situations where a polymerizing enzyme like XMAP215 and kinesin-8 mutually exclude each other from the MT tip. Moreover, we characterize the differences in the stochastic length dynamics between the two scenarios. While for the neutral scenario length is tightly controlled, length dynamics is intermittent for the inhibition scenario and exhibits extended periods of MT growth and shrinkage. On a broader perspective, the set of models established in this work quite generally suggest that mutual exclusion of molecules at the ends of cytoskeletal filaments is an important factor for filament dynamics and regulation.