Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles

Phillip A. Kohl, Chaeyeon Song, Bretton J. Fletcher, Rebecca L. Best, Christine Tchounwou, Ximena Garcia Arceo, Peter J. Chung, Herbert P. Miller, Leslie Wilson, Myung Chul Choi, Youli Li (), Stuart C. Feinstein and Cyrus R. Safinya ()
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Phillip A. Kohl: University of California, Santa Barbara
Chaeyeon Song: University of California, Santa Barbara
Bretton J. Fletcher: University of California, Santa Barbara
Rebecca L. Best: University of California, Santa Barbara
Christine Tchounwou: University of California, Santa Barbara
Ximena Garcia Arceo: University of California, Santa Barbara
Peter J. Chung: University of California, Santa Barbara
Herbert P. Miller: University of California, Santa Barbara
Leslie Wilson: University of California, Santa Barbara
Myung Chul Choi: Korea Advanced Institute of Science and Technology
Youli Li: University of California, Santa Barbara
Stuart C. Feinstein: University of California, Santa Barbara
Cyrus R. Safinya: University of California, Santa Barbara

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg2+ or Ca2+ divalent cations in mixtures containing αβ-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (Bws), a transient intermediate MT bundle phase (Bint), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αβ-tubulin oligomers in the IN are crosslinked by tau’s MT binding repeats, which also link αβ-tubulin oligomers to αβ-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.

Date: 2024
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DOI: 10.1038/s41467-024-46438-x

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