Intrinsically disordered proteins play key roles in cellular processes. Their conformational heterogeneity affords plasticity in molecular recognition. However, with plasticity, exposure of putative amyloid-forming motifs can drive ordered assembly leading to formation of large and insoluble assemblies linked to disease. We explore possible mechanisms for how IDPs mitigate assembly/aggregation. We propose that IDPs evolved to encode structural elements to directly control aggregation using metastable local structures that directly shield amyloid sequences. We test this idea in the context of the microtubule associated protein tau. Tauopathies are neurodegenerative diseases in which tau deposits as amyloids in patient brains. Although tau has been linked to neurodegeneration over 30 years ago, the detailed biophysical mechanisms of tau leading to aggregation remains poorly understood. We establish a structure-based mechanism that modulates aggregation of tau and rationalizes how mutations and splice isoforms of tau dictate the aggregation propensities of tau’s core amyloid motifs. We provide evidence for this model using multidisciplinary approaches including crosslink mass spectrometry, molecular dynamics simulations, intramolecular FRET, <i>in vitro</i> tau fragment systems, and cell models. We propose that tau’s amyloid motifs are sequestered within a local metastable b-turn structures we demonstrate that tau adopts metastable local structures that are perturbed by nearby disease-associated missense mutations, isomerization of critical prolines, or alternative splicing, leading to spontaneous aggregation. Through identification of these structural insights, our findings reveal novel strategies for the development of conformation-specific diagnostics and therapeutics for tau and other misfolding proteins.

Conformational insights into tau aggregation

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.