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Atomic model of microtubule-bound tau

Elizabeth H Kellogg, Nisreen M.A. Hejab, Simon Poepsel, Kenneth H Downing, Frank DiMaio, Eva Nogales

Preprint posted on 16 February 2018 https://www.biorxiv.org/content/early/2018/02/16/267153

Article now published in Science at http://dx.doi.org/10.1126/science.aat1780

How does Tau stabilize microtubules? Recent preprint uses cryo-EM and atomic modeling to reveal where on the microtubules lattice Tau binds and how its binding stabilizes them; one more piece added to the Tau-microtubule saga.

Selected by Satish Bodakuntla

Context: Tau is arguably the most important microtubule-associated protein (MAP), possibly due to its physiological role in microtubule regulation and its pathological relevance in several neurodegenerative diseases. Over the years, several studies investigated the mode of tau interaction with microtubules and how the interaction is impaired in disease conditions. Despite these extensive efforts, the molecular mechanisms of tau-microtubule interaction and its effect on microtubule stabilization remain to be fully understood. This preprint from Eva Nogales’ lab has added some valuable information to our understanding of the ‘Tau-microtubule saga’.

Key findings: The authors used state-of-the-art cryo-EM imaging to visualize full-length tau on microtubules. The obtained higher-resolution reconstruction images significantly expanded our previous knowledge on the Tau-microtubule interaction. Some of their key findings are

  1. The cryo-EM reconstruction of 4.1Å resolution revealed the presence of a narrow, discontinuous density of tau along the protofilament and next to the unstructured C-terminal tails of tubulin. While the observed position of tau is in agreement with previous studies, the density map of tau on microtubules corresponds to a fully extended chain, as opposed to previously proposed α-helical segment.
  2. Regardless of tau addition to the pre-formed microtubules or to polymerizing tubulin, the authors never observed tau density on the microtubule luminal surface, contradicting previous studies.
  3. This atomic model clearly showed the importance of the interacting residues in tau-tubulin binding and how they could possibly be mediating the binding.

Why I am interested in this preprint: Personally, I have been interested in the work of Eva Nogales’ lab for some time. This particular study from their lab caught my interest as they worked towards understanding the ‘tau-microtubule’ saga. Earlier studies, despite of their technical limitations, have contributed greatly to our understanding of tau-microtubule binding. In this preprint, taking advantage of state-of-the-art cryo-EM imaging, authors have not only added valuable information to this binding story, but have also revisited and discussed some of the previously published contradicting results.

 Questions the work raises: Authors observe the tau density close to the attachment site of unstructured C-terminal tails. This emphasizes a possible role of acidic C-terminal tails in altering the tau affinity. Is it then possible that posttranslational modifications on these acidic tails also influence the tau affinity?

Although the authors succeeded in modeling most of the residues in tau, they could not observe the PGGG motif in the reconstructions. Is it possible that PGGG motif is not involved in the tau-microtubule interaction? Or, like the authors explain, alternatively, is it possible that the motif needs flexibility to bind different conformational states of tubulin?

Related references

X. H. Li, J. A. Culver, E. Rhoades, Tau Binds to Multiple Tubulin Dimers with Helical Structure. J Am Chem Soc 137, 9218-9221 (2015).

S. Kar, J. Fan, M. J. Smith, M. Goedert, L. A. Amos, Repeat motifs of tau bind to the insides of microtubules in the absence of taxol. EMBO J 22, 70-77 (2003).

H. Kadavath et al., Folding of the Tau Protein on Microtubules. Angew Chem Int Ed Engl 54, 10347-10351 (2015).

A. W. P. Fitzpatrick et al., Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185-190 (2017).

J. Al-Bassam, R. S. Ozer, D. Safer, S. Halpain, R. A. Milligan, MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J Cell Biol 157, 1187-1196 (2002).

 

Tags: cryo-em, maps, microtubules, tau, tubulin modifications

Posted on: 27 April 2018 , updated on: 2 May 2018

Read preprint (1 votes)

Author's response

Eva Nogales shared

In addition to the full length protein, and several truncation constructs, we designed synthetic tau molecules with multiple copies of either the first or second microtubule-binding repeat that lend support to the idea that each repeat binds in a similar way, with R1 having the smallest footprint on the microtubule. These additional structures also strongly support the atomic model proposed, which relied on the combination of the cryo-EM density map with Rosseta modeling, by providing the same solution concerning the register of the repeat on the microtubule surface, and thus being consistent among all constructs examined.

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