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Tubulin tyrosination navigates the kinesin-1 motor domain to axons

Abstract

Neurons form distinctive axonal and dendritic compartments that are important for directional signaling, but the mechanisms that discriminate between axons and dendrites remain elusive. Previous studies have demonstrated that the kinesin-1 motor domain is capable of distinguishing the axon from dendrites. Here we found that the amino acid substitutions in the beta5-loop8 region transformed truncated kinesin-1 from a uni-destination (that is, the axon-specific destination) to a bi-destination (that is, axons and dendrites) state. Furthermore, tyrosinated tubulins that are abundant in somatodendrites prevent the wild-type kinesin-1 from binding to microtubules, whereas the bi-destination–type kinesin-1 does not have this inhibition. Consistently, inhibition of tubulin tyrosination in rat hippocampal neurons resulted in the distribution of truncated kinesin-1 in both axons and dendrites. Our study identifies a molecular mechanism that discriminates the axonal microtubules from somatodendritic microtubules, as well as a previously unknown linkage between tubulin modification and polarized trafficking in neurons.

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Figure 1: The β5-L8 region is involved in the polarized trafficking of the kinesin-1 motor domain.
Figure 2: The bi-destination type of kinesin-1 shows higher affinity to brain microtubules.
Figure 3: The β5-L8 region of kinesin-1 is required for the recognition of tubulin tyrosination signals.
Figure 4: Tubulin tyrosination is required for the polarized trafficking of the kinesin-1 motor domain to the axon.
Figure 5: Kinesin-1 inhibitions cause polarity defects in neurons.
Figure 6: Polarized transport of kinesin-1 is required for maintenance of neuronal polarity.

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Acknowledgements

We are grateful to M. Kikkawa for his help with the electron microscopy and for valuable discussions. We also thank A. Bonni and N. Ohkawa for critical reading of the manuscript, T. Funatsu, S. Uemura and M. Tsunoda for valuable discussions, K. Yasutake and M. Arai for help with primary cultures, Y. Hatanaka and M. Takamatsu for help with preparing constructs, and the Department of Molecular Anatomy, Hamamatsu University School of Medicine and the Molecular Gerontology Group at the Mitsubishi Kagaku Institute of Life Sciences for various forms of help. This work was supported in part by Grants-In-Aid for Young Scientists S (M.S.) and B (Y.K.) and by a grant from the Mitsubishi Kagaku Institute of Life Sciences.

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Y.K. conducted all experiments with technical assistances and wrote the manuscript. M.S. supervised the project.

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Correspondence to Yoshiyuki Konishi or Mitsutoshi Setou.

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Konishi, Y., Setou, M. Tubulin tyrosination navigates the kinesin-1 motor domain to axons. Nat Neurosci 12, 559–567 (2009). https://doi.org/10.1038/nn.2314

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