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; Cyrus R Safinya

doi:10.1038/s41467-024-46438-x

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

Nat Commun. 2024 Mar 15;15(1):2362. doi: 10.1038/s41467-024-46438-x.

Authors

Phillip A Kohl^#¹, Chaeyeon Song^#^{2

3

4

5

6}, Bretton J Fletcher^#^{2

3

4

5}, Rebecca L Best^{4

7

8}, Christine Tchounwou^{2

3

4

5}, Ximena Garcia Arceo^{5

9}, Peter J Chung^{2

3

4

5

10}, Herbert P Miller⁴, Leslie Wilson^{4

7}, Myung Chul Choi¹¹, Youli Li¹², Stuart C Feinstein^{4

7}, Cyrus R Safinya^{13

14

15

16}

Affiliations

¹ Materials Research Laboratory, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.
² Materials Department, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.
³ Biomolecular Science and Engineering, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.
⁴ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
⁵ Department of Physics, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.
⁶ Amorepacific R&I Center, Yongin, 17074, Republic of Korea.
⁷ Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.
⁸ Serimmune Inc., 150 Castilian Dr., Goleta, CA, 93117, USA.
⁹ Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA, 93106, USA.
¹⁰ Department of Physics and Astronomy, University of Southern California, Los Angeles, CA, 90089, USA.
¹¹ Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon, 34141, Korea.
¹² Materials Research Laboratory, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA. youli@mrl.ucsb.edu.
¹³ Materials Department, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA. cyrussafinya@ucsb.edu.
¹⁴ Biomolecular Science and Engineering, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA. cyrussafinya@ucsb.edu.
¹⁵ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA. cyrussafinya@ucsb.edu.
¹⁶ Department of Physics, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA. cyrussafinya@ucsb.edu.

^# Contributed equally.

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 (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.

MeSH terms

Humans
Microtubules / metabolism
Scattering, Small Angle
Tubulin* / metabolism
X-Ray Diffraction
tau Proteins* / metabolism

Substances

tau Proteins
Tubulin
MAPT protein, human

Abstract

MeSH terms

Substances

Grants and funding