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

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.
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  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:
OSTI Identifier:
Grant/Contract Number:
FG02-06ER46314; DMR-1401784; R01-NS13560; R01-NS35010; 2014-R1A1A2A16055715; 2011-0031931; 2011-0031931;
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Nature Publishing Group
Research Org:
Univ. of California, Santa Barbara, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); US National Science Foundation (NSF); US National Inst. of Health (NIH)
Country of Publication:
United States