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Title: Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment

Abstract

Tau, an intrinsically disordered protein confined to neuronal axons, binds to and regulates microtubule dynamics. Although there have been observations of string-like microtubule fascicles in the axon initial segment (AIS) and hexagonal bundles in neurite-like processes in non-neuronal cells overexpressing Tau, cell-free reconstitutions have not replicated either geometry. Here we map out the energy landscape of Tau-mediated, GTP-dependent ‘active’ microtubule bundles at 37°C, as revealed by synchrotron SAXS and TEM. Widely spaced bundles (wall-to-wall distance Dw–w≈25–41nm) with hexagonal and string-like symmetry are observed, the latter mimicking bundles found in the AIS. A second energy minimum (Dw–w≈16–23nm) is revealed under osmotic pressure. The wide spacing results from a balance between repulsive forces, due to Tau’s projection domain (PD), and a stabilizing sum of transient sub-kBT cationic/anionic charge–charge attractions mediated by weakly penetrating opposing PDs. In the end, we find that this landscape would be significantly affected by charge-altering modifications of Tau associated with neurodegeneration.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Univ. of California, Santa Barbara, CA (United States)
  2. Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea, Republic of). Dept. of Bio and Brain Engineering
Publication Date:
Research Org.:
Univ. of California, Santa Barbara, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF); National Institutes of Health (NIH)
OSTI Identifier:
1326678
Grant/Contract Number:  
FG02-06ER46314; DMR-1401784; R01-NS13560; R01-NS35010; 2014-R1A1A2A16055715; 2011-0031931
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Chung, Peter J., Song, Chaeyeon, Deek, Joanna, Miller, Herbert P., Li, Youli, Choi, Myung Chul, Wilson, Leslie, Feinstein, Stuart C., and Safinya, Cyrus R. Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment. United States: N. p., 2016. Web. doi:10.1038/ncomms12278.
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Chung, Peter J., Song, Chaeyeon, Deek, Joanna, Miller, Herbert P., Li, Youli, Choi, Myung Chul, Wilson, Leslie, Feinstein, Stuart C., & Safinya, Cyrus R. Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment. United States. https://doi.org/10.1038/ncomms12278
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Chung, Peter J., Song, Chaeyeon, Deek, Joanna, Miller, Herbert P., Li, Youli, Choi, Myung Chul, Wilson, Leslie, Feinstein, Stuart C., and Safinya, Cyrus R. Mon . "Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment". United States. https://doi.org/10.1038/ncomms12278. https://www.osti.gov/servlets/purl/1326678.
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@article{osti_1326678,
title = {Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment},
author = {Chung, Peter J. and Song, Chaeyeon and Deek, Joanna and Miller, Herbert P. and Li, Youli and Choi, Myung Chul and Wilson, Leslie and Feinstein, Stuart C. and Safinya, Cyrus R.},
abstractNote = {Tau, an intrinsically disordered protein confined to neuronal axons, binds to and regulates microtubule dynamics. Although there have been observations of string-like microtubule fascicles in the axon initial segment (AIS) and hexagonal bundles in neurite-like processes in non-neuronal cells overexpressing Tau, cell-free reconstitutions have not replicated either geometry. Here we map out the energy landscape of Tau-mediated, GTP-dependent ‘active’ microtubule bundles at 37°C, as revealed by synchrotron SAXS and TEM. Widely spaced bundles (wall-to-wall distance Dw–w≈25–41nm) with hexagonal and string-like symmetry are observed, the latter mimicking bundles found in the AIS. A second energy minimum (Dw–w≈16–23nm) is revealed under osmotic pressure. The wide spacing results from a balance between repulsive forces, due to Tau’s projection domain (PD), and a stabilizing sum of transient sub-kBT cationic/anionic charge–charge attractions mediated by weakly penetrating opposing PDs. In the end, we find that this landscape would be significantly affected by charge-altering modifications of Tau associated with neurodegeneration.},
doi = {10.1038/ncomms12278},
journal = {Nature Communications},
number = ,
volume = 7,
place = {United States},
year = {Mon Jul 25 00:00:00 EDT 2016},
month = {Mon Jul 25 00:00:00 EDT 2016}
}
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https://doi.org/10.1038/ncomms12278
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Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
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Measurement of the repulsive force between polyelectrolyte molecules in ionic solution: hydration forces between parallel DNA double helices.
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Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.
journal, July 1986

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Domain Conformation of Tau Protein Studied by Solution Small-Angle X-ray Scattering †
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The axon initial segment and the maintenance of neuronal polarity
journal, July 2010

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Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules
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Random-coil behavior and the dimensions of chemically unfolded proteins
journal, August 2004

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journal, October 1994

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  • Biochemistry, Vol. 33, Issue 32
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Neurofilament networks: Salt-responsive hydrogels with sidearm-dependent phase behavior
journal, July 2016

  • Deek, Joanna; Chung, Peter J.; Safinya, Cyrus R.
  • Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1860, Issue 7
  • DOI: 10.1016/j.bbagen.2016.03.018
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    Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects
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    Axonal transport: Driving synaptic function
    journal, October 2019

    The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology
    journal, November 2019

    D+ : software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures
    journal, February 2019

    Tau can switch microtubule network organizations: from random networks to dynamic and stable bundles
    journal, January 2018

    • Prezel, Elea; Elie, Auréliane; Delaroche, Julie
    • Molecular Biology of the Cell, Vol. 29, Issue 2
    • DOI: 10.1091/mbc.e17-06-0429

    Microtubules: From understanding their dynamics to using them as potential therapeutic targets
    journal, November 2018

    • Ilan, Yaron
    • Journal of Cellular Physiology, Vol. 234, Issue 6
    • DOI: 10.1002/jcp.27978

    Tau can switch microtubule network organizations: from random networks to dynamic and stable bundles
    journal, January 2018

    • Prezel, Elea; Elie, Auréliane; Delaroche, Julie
    • Molecular Biology of the Cell, Vol. 29, Issue 2
    • DOI: 10.1091/mbc.e17-06-0429
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