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Title | A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms. |
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Journal, issue, pages | ACS Cent Sci, Vol. 7, Issue 12, Page 1986-1995, Year 2021 |
Publish date | Dec 22, 2021 |
Authors | Z Faidon Brotzakis / Philip R Lindstedt / Ross J Taylor / Dillon J Rinauro / Nicholas C T Gallagher / Gonçalo J L Bernardes / Michele Vendruscolo / |
PubMed Abstract | 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 ...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. |
External links | ACS Cent Sci / PubMed:34963892 / PubMed Central |
Methods | EM (single particle) |
Resolution | 4.1 Å |
Structure data | PDB-7pqc: PDB-7pqp: |
Chemicals | ChemComp-GDP: ChemComp-GTP: ChemComp-MG: |
Source |
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Keywords | STRUCTURAL PROTEIN / Complex |