Intrinsically Disordered Proteins and Neurodegenerative Diseases

Early Fibrilization of Tau is Preceded by the Formation of Dynamic Aggregation Intermediates

A. Pavlova, C. Cheng, M. Kinnebrew, J. Lew, F. Dahlquist, S. Han, "Protein structural and surface water rearrangement constitute major events in the earliest aggregation stages of tau", Proc. Natl. Acad. Sci. 113 (2) (2016) E127-E136 PMCID: PMC4720316; DOI:10.1073/pnas.1504415113

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 Δ tau187 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 Δ tau187. Within minutes of initiated aggregation, the majority of Δ tau187 that is initially homogeneously hydrated undergoes structural transformations to form partially structured aggregation intermediat es. This is reflected in the disper- sion of surface water dynamics that is distinct around the third re- peat 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 interme- diates 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 tha t precedes, and likely facilitates, fibril formation and growth.