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Publication Abstract from PubMed

Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.

A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms.,Brotzakis ZF, Lindstedt PR, Taylor RJ, Rinauro DJ, Gallagher NCT, Bernardes GJL, Vendruscolo M ACS Cent Sci. 2021 Dec 22;7(12):1986-1995. doi: 10.1021/acscentsci.1c00585. Epub , 2021 Dec 8. PMID:34963892^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.