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

Kohl, Phillip A.; Song, Chaeyeon; Fletcher, Bretton J.; Best, Rebecca L.; Tchounwou, Christine; Garcia Arceo, Ximena; Chung, Peter J.; Miller, Herbert P.; Wilson, Leslie; Choi, Myung Chul; Li, Youli; Feinstein, Stuart C.; Safinya, Cyrus R.

doi:10.1038/s41467-024-46438-x

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

Journal Article · Fri Mar 15 00:00:00 EDT 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-46438-x· OSTI ID:2324692

Kohl, Phillip A.; Song, Chaeyeon; Fletcher, Bretton J.;

; Tchounwou, Christine; Garcia Arceo, Ximena;

; Miller, Herbert P.; Wilson, Leslie; Choi, Myung Chul;

; Feinstein, Stuart C.;

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 Mg ²⁺ or Ca ²⁺ 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 (B _ws ), a transient intermediate MT bundle phase (B _int ), 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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: FG02-06ER46314

OSTI ID:: 2324692

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 15 Journal Issue: 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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