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Nat Commun. 2016 Jul 25;7:12278. doi: 10.1038/ncomms12278.

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

Author information

1
Materials Department, Physics Department, Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
2
Chemistry and Biochemistry Department, University of California, Santa Barbara, California 93106, USA.
3
Neuroscience Research Institute and Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
4
Materials Research Laboratory, University of California, Santa Barbara, California 93106, USA.
5
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

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

PMID:
27452526
PMCID:
PMC4962469
DOI:
10.1038/ncomms12278
[Indexed for MEDLINE]
Free PMC Article

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