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bioRxiv · 10.1101/163394

Inert and seed-competent tau monomers elucidate the structural origins of aggregation

Mirbaha, H.·Morozova, O. A.·Ruff, K. M.·Sharma, A.·Pappu, R. V.·Colby, D. W.·Mirzaei, H.·Joachimiak, L. A.·Diamond, M. I.
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Abstract

Tauopathies feature progressive accumulation of tau amyloids. Pathology may begin when these amplify from a protein template, or seed, whose structure is unknown. We have purified and characterized distinct forms of tau monomer--inert (Mi) and seed-competent (Ms). Recombinant Ms triggered intracellular tau aggregation, induced tau fibrillization in vitro, and self-assembled. Ms from Alzheimers disease also seeded aggregation and self-assembled in vitro to form seed-competent multimers. We used crosslinking with mass spectrometry to probe structural differences in Mi vs. Ms. Crosslinks informed models of local peptide structure within the repeat domain which suggest relative inaccessibility of residues that drive aggregation (VQIINK/VQIVYK) in Mi, and exposure in Ms. Limited proteolysis supported this idea. Although tau monomer has been considered to be natively unstructured, our findings belie this assumption and suggest that initiation of pathological aggregation could begin with conversion of tau monomer from an inert to a seed-competent form.

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Mirbaha, H., Morozova, O. A., Ruff, K. M., Sharma, A., Pappu, R. V., Colby, D. W., Mirzaei, H., Joachimiak, L. A., Diamond, M. I.. 2017-07-14. Inert and seed-competent tau monomers elucidate the structural origins of aggregation. https://doi.org/10.1101/163394

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