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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Axon Initial Segment / metabolism*
  • Axon Initial Segment / ultrastructure
  • Cattle
  • Microtubules / metabolism*
  • Microtubules / ultrastructure
  • Osmotic Pressure
  • Protein Domains
  • Scattering, Small Angle
  • Thermodynamics
  • X-Ray Diffraction
  • tau Proteins / chemistry
  • tau Proteins / metabolism*

Substances

  • tau Proteins