Full-length tau seeded by C-shaped tau fibrils is conformationally variable.

A number of neurodegenerative amyloid proteins have been found to adopt disease-specific structures in the human brain. This prion-like propagation of the amyloid structure requires recruitment of soluble monomers containing various posttranslational modifications to adopt the same structure as the fibril seeds. To understand the structural fidelity of seeding for amyloid proteins that possess large intrinsically disordered regions, here we investigate the seeding of a full-length phospho-mimetic tau protein, 4E tau, using a truncated tau construct that adopts the C-shaped Alzheimer's disease (AD) fold. Sedimentation gels indicate that four replicas of cross-seeded reactions all showed accelerated fibrillization kinetics. However, solid-state NMR spectra indicate that these cross-seeded samples have structurally variable cores, all of which differ from the AD fold of the seed fibrils, some of which resemble the unseeded triple-stranded structure of the full-length protein, and two of which contain two polymorphs. INEPT NMR spectra indicate that these cross-seeded replicas have similar dynamic disorder for their fuzzy coat, which differs from the dynamics of unseeded full-length 4E tau. These results indicate that accelerated fibrillization kinetics do not necessarily correlate with faithful amplification of the seed structure, and surface-catalyzed nucleation of full-length tau with large intrinsically disordered regions leads to structural polymorphism and structural evolution from the seed fibrils.