Inert and seed-competent tau monomers suggest structural origins of aggregation

Hilda Mirbaha, Dailu Chen, Olga A. Morazova, Kiersten M. Ruff, Apurwa M. Sharma, Xiaohua Liu, Mohammad Goodarzi, Rohit V. Pappu, David W. Colby, Hamid Mirzaei, Lukasz A. Joachimiak, Marc I. Diamond

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 Alzheimer’s 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.

Original languageEnglish (US)
Article numbere36584
JournaleLife
Volume7
DOIs
StatePublished - Jul 10 2018

Fingerprint

Seed
Seeds
Agglomeration
Monomers
Tauopathies
Proteolysis
Pathology
Amyloid
Crosslinking
Mass spectrometry
Mass Spectrometry
Alzheimer Disease
Peptides
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Mirbaha, H., Chen, D., Morazova, O. A., Ruff, K. M., Sharma, A. M., Liu, X., ... Diamond, M. I. (2018). Inert and seed-competent tau monomers suggest structural origins of aggregation. eLife, 7, [e36584]. https://doi.org/10.7554/eLife.36584

Inert and seed-competent tau monomers suggest structural origins of aggregation. / Mirbaha, Hilda; Chen, Dailu; Morazova, Olga A.; Ruff, Kiersten M.; Sharma, Apurwa M.; Liu, Xiaohua; Goodarzi, Mohammad; Pappu, Rohit V.; Colby, David W.; Mirzaei, Hamid; Joachimiak, Lukasz A.; Diamond, Marc I.

In: eLife, Vol. 7, e36584, 10.07.2018.

Research output: Contribution to journalArticle

Mirbaha, H, Chen, D, Morazova, OA, Ruff, KM, Sharma, AM, Liu, X, Goodarzi, M, Pappu, RV, Colby, DW, Mirzaei, H, Joachimiak, LA & Diamond, MI 2018, 'Inert and seed-competent tau monomers suggest structural origins of aggregation', eLife, vol. 7, e36584. https://doi.org/10.7554/eLife.36584
Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X et al. Inert and seed-competent tau monomers suggest structural origins of aggregation. eLife. 2018 Jul 10;7. e36584. https://doi.org/10.7554/eLife.36584
Mirbaha, Hilda ; Chen, Dailu ; Morazova, Olga A. ; Ruff, Kiersten M. ; Sharma, Apurwa M. ; Liu, Xiaohua ; Goodarzi, Mohammad ; Pappu, Rohit V. ; Colby, David W. ; Mirzaei, Hamid ; Joachimiak, Lukasz A. ; Diamond, Marc I. / Inert and seed-competent tau monomers suggest structural origins of aggregation. In: eLife. 2018 ; Vol. 7.
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