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

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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 degrees C, as revealed by synchrotron SAXS and TEM. Widely spaced bundles (wall-to-wall distance Dw-w approximate to 25-41 nm) with hexagonal and string-like symmetry are observed, the latter mimicking bundles found in the AIS. A second energy minimum (Dw-w approximate to 16-23 nm) 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(B)T cationic/anionic charge-charge attractions mediated by weakly penetrating opposing PDs. This landscape would be significantly affected by charge-altering modifications of Tau associated with neurodegeneration
Publisher
NATURE PUBLISHING GROUP
Issue Date
2016-07
Language
English
Article Type
Article
Keywords

X-RAY-SCATTERING; PROTEIN-TAU; ALZHEIMER-DISEASE; AQUEOUS-SOLUTIONS; TUBULIN; DOMAINS; PHOSPHORYLATION; POLYMERIZATION; CONFORMATION; ORGANIZATION

Citation

NATURE COMMUNICATIONS, v.7, no.12, pp.278

ISSN
2041-1723
DOI
10.1038/ncomms12278
URI
http://hdl.handle.net/10203/212873
Appears in Collection
BiS-Journal Papers(저널논문)
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