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

Peter J. Chung, Chaeyeon Song, Joanna Deek, Herbert P. Miller, Youli Li, Myung Chul Choi, Leslie Wilson, Stuart C. Feinstein and Cyrus R. Safinya ()
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Peter J. Chung: Molecular, Cellular, University of California
Chaeyeon Song: Molecular, Cellular, University of California
Joanna Deek: University of California
Herbert P. Miller: Neuroscience Research Institute and Molecular, Cellular, University of California
Youli Li: Materials Research Laboratory, University of California
Myung Chul Choi: Korea Advanced Institute of Science and Technology (KAIST)
Leslie Wilson: Neuroscience Research Institute and Molecular, Cellular, University of California
Stuart C. Feinstein: Neuroscience Research Institute and Molecular, Cellular, University of California
Cyrus R. Safinya: Molecular, Cellular, University of California

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12278

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