title: Protein structural and surface water rearrangement constitute major events in the earliest aggregation stages of tau.
abstract: Protein aggregation plays a critical role in the pathogenesis of neurodegenerative diseases, and the mechanism of its progression is poorly understood. Here, we examine the structural and dynamic characteristics of transiently evolving protein aggregates under ambient conditions by directly probing protein surface water diffusivity, local protein segment dynamics, and interprotein packing as a function of aggregation time, along the third repeat domain and C terminus of Δtau187 spanning residues 255-441 of the longest isoform of human tau. These measurements were achieved with a set of highly sensitive magnetic resonance tools that rely on site-specific electron spin labeling of Δtau187. Within minutes of initiated aggregation, the majority of Δtau187 that is initially homogeneously hydrated undergoes structural transformations to form partially structured aggregation intermediates. This is reflected in the dispersion of surface water dynamics that is distinct around the third repeat domain, found to be embedded in an intertau interface, from that of the solvent-exposed C terminus. Over the course of hours and in a rate-limiting process, a majority of these aggregation intermediates proceed to convert into stable β-sheet structured species and maintain their stacking order without exchanging their subunits. The population of β-sheet structured species is >5% within 5 min of aggregation and gradually grows to 50-70% within the early stages of fibril formation, while they mostly anneal block-wisely to form elongated fibrils. Our findings suggest that the formation of dynamic aggregation intermediates constitutes a major event occurring in the earliest stages of tau aggregation that precedes, and likely facilitates, fibril formation and growth.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106;
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlova
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106;
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: College of Creative Studies, Biology Department, University of California, Santa Barbara, CA 93106;
authors.forename: Maia
authors.initials: M
authors.lastname: Kinnebrew
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106;
authors.forename: John
authors.initials: J
authors.lastname: Lew
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106; Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106;
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Dahlquist
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106; Department of Chemical Engineering, University of California, Santa Barbara, CA 93106 songi@chem.ucsb.edu.
authors.forename: Songi
authors.initials: S
authors.lastname: Han
mesh_terms: D003198:Computer Simulation; D020285:Cryoelectron Microscopy; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D050505:Mutant Proteins / Q000737:chemistry; D066329:Protein Aggregates; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D013113:Spin Labels; D013997:Time Factors; D014867:Water / Q000737:chemistry*; D016875:tau Proteins / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D050505:Mutant Proteins; D066329:Protein Aggregates; D021122:Protein Subunits; D013113:Spin Labels; D016875:tau Proteins; D014867:Water
keywords: Alzheimer's disease; amyloid formation; biological water; site-directed spin labeling; soluble oligomers