Regulation of axonal transport includes control of the microtubule-associated protein Tau. Site-specific pseudophosphorylation of Tau modulates its ability to inhibit kinesin-1 motility by both shifting its static–dynamic state binding equilibrium toward the dynamic state and reducing its affinity for microtubules.

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The length of KIF18A's neck linker permits navigation of obstacles along K-fibers within the mitotic spindle and is required for the timely alignment and segregation of mitotic chromosomes.

Microtubule-associated proteins (MAPs) modulate the motility of kinesin and dynein along microtubules to control the transport of vesicles and organelles. The neuronal MAP tau inhibits kinesin-dependent transport. Phosphorylation of tau at tyrosine 18 by fyn kinase results in weakened inhibition of kinesin-1. We examined the motility of early endosomes and lysosomes in cells expressing wild-type (WT) tau and phosphomimetic Y18E tau. We quantified the effects on motility as a function of the tau expression level. Lysosome motility is strongly inhibited by tau. Y18E tau preferentially inhibits lysosomes in the cell periphery, while centrally located lysosomes are less affected. Early endosomes are more sensitive to tau than lysosomes, and are inhibited by both WT and Y18E tau. Our results show that different cargoes have disparate responses to tau, likely governed by the types of kinesin motors driving their transport. In support of this model, kinesin-1 and -3 are strongly inhibited by tau while kinesin-2 and dynein are less affected. In contrast to kinesin-1, we find that kinesin-3 is strongly inhibited by phosphorylated tau. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

Axonal transport is a highly regulated cellular process responsible for site-specific neuronal cargo delivery. This process is mediated in part by KIF1A, a member of the kinesin-3 family of molecular motors. It is imperative that KIF1A's highly efficient, superprocessive motility along microtubules is tightly regulated as misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases. However, the regulatory mechanisms responsible for KIF1A's motility, and subsequent proper spatiotemporal cargo delivery, are largely unknown. One potential regulatory mechanism of KIF1A motility is through the posttranslational modifications (PTMs) of axonal microtubules. These PTMs, often occurring on the C-terminal tails of the microtubule tracks, act as molecular "traffic signals" helping to direct kinesin motor cargo delivery. Occurring on neuronal microtubules, C-terminal tail polygutamylation is known to be important for KIF1A cargo transport. KIF1A's initial interaction with microtubule C-terminal tails is facilitated by the K-loop, a positively charged surface loop of the KIF1A motor domain. However, the K-loop's role in KIF1A motility and response to perturbations in C-terminal tail polyglutamylation is underexplored. Using single-molecule imaging, we present evidence of KIF1A's previously unreported pausing behavior on multiple microtubule structures. Further analysis revealed that these pauses link multiple processive segments together, contributing to KIF1A's characteristic superprocessive run length. We further demonstrate that KIF1A pausing is mediated by a Kloop/polyglutamylated C-terminal tail interaction and is a regulatory mechanism of KIF1A motility. In summary, we introduce a new mechanism of KIF1A motility regulation, providing further insight into KIF1A's role in axonal transport.