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J Biol Chem. 2019 Apr 19;294(16):6353-6363. doi: 10.1074/jbc.RA118.005765. Epub 2019 Feb 15.

Polyglutamylation of tubulin's C-terminal tail controls pausing and motility of kinesin-3 family member KIF1A.

Author information

1
From the Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405 and.
2
the Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
3
From the Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405 and cberger@uvm.edu.

Abstract

The kinesin-3 family member KIF1A plays a critical role in site-specific neuronal cargo delivery during axonal transport. KIF1A cargo is mislocalized in many neurodegenerative diseases, indicating that KIF1A's highly efficient, superprocessive motility along axonal microtubules needs to be tightly regulated. One potential regulatory mechanism may be through posttranslational modifications (PTMs) of axonal microtubules. These PTMs often occur on the C-terminal tails of the microtubule tracks, act as molecular "traffic signals" helping to direct kinesin motor cargo delivery, and include C-terminal tail polyglutamylation important for KIF1A cargo transport. KIF1A initially interacts with microtubule C-terminal tails through its K-loop, a positively charged surface loop of the KIF1A motor domain. However, the role of the K-loop in KIF1A motility and response to perturbations in C-terminal tail polyglutamylation is underexplored. Using single-molecule imaging, we present evidence that KIF1A pauses on different microtubule lattice structures, linking multiple processive segments together and contributing to KIF1A's characteristic superprocessive run length. Furthermore, modifications of the KIF1A K-loop or tubulin C-terminal tail polyglutamylation reduced KIF1A pausing and overall run length. These results suggest a new mechanism to regulate KIF1A motility via pauses mediated by K-loop/polyglutamylated C-terminal tail interactions, providing further insight into KIF1A's role in axonal transport.

KEYWORDS:

K-loop; KIF1A; cytoskeleton; kinesin; microtubule; molecular motor; neuron; polyglutamylation; post-translational modification (PTM); single-molecule biophysics

PMID:
30770469
PMCID:
PMC6484136
[Available on 2020-04-19]
DOI:
10.1074/jbc.RA118.005765

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