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

Chung, Peter J.; Song, Chaeyeon; Deek, Joanna; Miller, Herbert P.; Li, Youli; Choi, Myung Chul; Wilson, Leslie; Feinstein, Stuart C.; Safinya, Cyrus R.

doi:10.1038/ncomms12278

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

Journal Article · Mon Jul 25 00:00:00 EDT 2016 · Nature Communications

DOI:https://doi.org/10.1038/ncomms12278· OSTI ID:1326678

Chung, Peter J. ^[1]; Song, Chaeyeon ^[1]; Deek, Joanna ^[1]; Miller, Herbert P. ^[1]; Li, Youli ^[1]; Choi, Myung Chul ^[2]; Wilson, Leslie ^[1]; Feinstein, Stuart C. ^[1]; Safinya, Cyrus R. ^[1]

Univ. of California, Santa Barbara, CA (United States)
Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea, Republic of). Dept. of Bio and Brain Engineering

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 D_w–w≈25–41nm) with hexagonal and string-like symmetry are observed, the latter mimicking bundles found in the AIS. A second energy minimum (D_w–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-k_BT 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.

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Research Organization:: Univ. of California, Santa Barbara, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF); National Institutes of Health (NIH)

Grant/Contract Number:: FG02-06ER46314; DMR-1401784; R01-NS13560; R01-NS35010; 2014-R1A1A2A16055715; 2011-0031931

OSTI ID:: 1326678

Journal Information:: Nature Communications, Vol. 7; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 32 works

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Axonal transport: Driving synaptic function Guedes-Dias, Pedro; Holzbaur, Erika L. F. Science, Vol. 366, Issue 6462 https://doi.org/10.1126/science.aaw9997	journal	October 2019
The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology Hahn, Ines; Voelzmann, André; Liew, Yu-Ting Neural Development, Vol. 14, Issue 1 https://doi.org/10.1186/s13064-019-0134-0	journal	November 2019
Tau Phosphorylation Rates Measured by Mass Spectrometry Differ in the Intracellular Brain vs. Extracellular Cerebrospinal Fluid Compartments and Are Differentially Affected by Alzheimer’s Disease Barthélemy, Nicolas R.; Mallipeddi, Nipun; Moiseyev, Paul Frontiers in Aging Neuroscience, Vol. 11 https://doi.org/10.3389/fnagi.2019.00121	journal	May 2019
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