AI Article Synopsis

  • In Alzheimer's disease and related tauopathies, the tau protein accumulates in the brain, leading to neurodegeneration, and this process is influenced by how tau is modified through ubiquitination, particularly at specific lysine residues (K311 and K317).
  • The study investigated how adding ubiquitin to tau at these residues affects its ability to form structured fibrils, finding that modifications at K317 hinder fibril formation and that the presence of double ubiquitination could prevent the formation of certain liquid droplet intermediates.
  • Overall, the research suggests that site-specific ubiquitination alters tau's transition into harmful amyloid aggregates, providing insights into the complex mechanisms underlying tau pathology in neurodegenerative diseases.

Article Abstract

In Alzheimer's disease and related disorders called tauopathies, the microtubule-associated protein tau accumulates in the brain in the form of amyloid-like supramolecular filaments. As an intrinsically disordered protein, tau undergoes many post-translational modifications, including ubiquitination. Alterations to the levels of ubiquitination of tau have been observed at various stages of neurodegenerative conditions. We focus on proteoform-specific interrogations to obtain mechanistic insight into the effects of ubiquitination on disease-related conformational transitions of tau. Single and double ubiquitination of tau at residues Lys311 and Lys317 is strongly associated with pathological conditions. In this study, we leveraged disulfide-directed chemistry to install ubiquitin at one or both of those positions in the isolated microtubule-binding repeat domain of tau. We obtained homogeneously modified tau proteins and observed that they retained disordered character in solution. We found that ubiquitination in position 317 (with or without ubiquitination in position 311) impaired the formation of ordered fibrillar structures via oligomeric intermediates. Since the transition to fibrillar species may proceed via an alternative condensation pathway involving liquid droplet intermediates, we further tested the ability of the ubiquitinated proteoforms to phase separate. Single monoubiquitinated tau species were able to coacervate, however no liquid droplets were observed for the double ubiquitinated form. Taken together, the data indicate that double ubiquitination in the third repeat of tau disfavors the formation of amyloid aggregates by distinct mechanisms, suggesting that the presence of ubiquitinated residues 311 and 317 in insoluble tau may result from modifications in advanced stages of aggregation. These findings contribute to our understanding of the influence of site-specific ubiquitination on the pathological conformational transitions of a prototypical intrinsically disordered protein.

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http://dx.doi.org/10.1016/j.bioorg.2023.106347DOI Listing

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