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.

Limited Resources Induce Bistability in Microtubule Length Regulation

“…2(e)]. This is fundamentally different from MT length regulation with unlimited resources [14,15], where only one stationary state of finite length is observed. A What physical processes determine MT length and lead to bistability?…”

“…This is facilitated by a density gradient on the MT, caused by the interplay between the processive motion of Kip3 along the MT and its depolymerase activity at the plus end, which effectively enables the MT to "sense" its own length [12,13]. In combination with spontaneous MT polymerization, the Kip3 gradient leads to a length regulation mechanism [14,15].Here, we explore the combined effect of limited resources and Kip3-induced depolymerization on the length regulation of MTs. As seen in theoretical studies on the collective motion of molecular motors, resource limitation affects the density profile on the MT: regions of low and high motor density separate, as a localized domain wall emerges on the MT [16][17][18][19].…”

“…This is facilitated by a density gradient on the MT, caused by the interplay between the processive motion of Kip3 along the MT and its depolymerase activity at the plus end, which effectively enables the MT to "sense" its own length [12,13]. In combination with spontaneous MT polymerization, the Kip3 gradient leads to a length regulation mechanism [14,15].…”

“…To investigate the impact of limited resources on MT dynamics, we employ a driven diffusive lattice gas model [30][31][32] for spontaneous MT polymerization and kinesincatalyzed MT depolymerization [14,15], as illustrated in Fig. 1.…”

Theme Issue in memory of Tom Duke

“…The contribution by Reese et al [8] studies the principles of microtubule length regulation by proteins that interact with the growing tip. They investigate the interplay of microtubule depolymerases and polymerases and suggest scenarios in which length is either tightly regulated or in which strong length fluctuations occur.…”