Regulation of KIF1A Behavior and Motility via Tau'S Structural Dynamics

Abstract

The kinesin-3 family member KIF1A is an essential mediator of anterograde axonal transport. Characteristically, KIF1A is responsible for long-range spatiotemporally regulated cargo delivery, aided by its highly processive behavior on axonal microtubules. Our lab has recently characterized a mechanism for a unique pausing behavior of KIF1A in between processive segments on the microtubule. This behavior, mediated through an interaction between the KIF1A K-loop and the polyglutamylated C-terminal tails of tubulin, helps us further understand how KIF1A conducts long-range cargo transport. However, how this pausing behavior is influenced by other regulatory factors on the microtubule is an unexplored concept. A potential regulator of KIF1A pausing and subsequent motility is the microtubule associated protein Tau, due to the known interaction of Tau's diffusive binding state with the C-terminal tails of tubulin. While our lab has characterized the mechanisms by which Tau's binding state regulates the motility of kinesin-1 and kinesin-2 family members, Tau's regulatory capabilities of KIF1A are unexplored at the behavioral level. Using single-molecule imaging, we have identified Tau-mediated regulation of KIF1A pausing behavior and motility. Specifically, we have elucidated the competitive interaction between Tau and KIF1A for the C-terminal tails of tubulin. This competition introduces a new mechanism of Tau-mediated kinesin regulation by inhibiting KIF1A's ability to use pauses to connect multiple processive segments into a longer run length. Moreover, we have correlated this regulatory mechanism to Tau's structural dynamics, further elucidating the function of Tau's diffusive and static behavioral state on the microtubule surface.