Conformational Basis for Asymmetric Seeding Barrier in Filaments of Three- and Four-Repeat Tau

Tau pathology in Alzheimer’s disease is intimately
linked
to the deposition of proteinacious filaments, which akin to infectious
prions, have been proposed to spread via seeded conversion. Here we
use double electron–electron resonance (DEER) spectroscopy
in combination with extensive computational analysis to show that
filaments of three- (3R) and four-repeat (4R) tau are conformationally
distinct. Distance measurements between spin labels in the third repeat,
reveal tau amyloid filaments as ensembles of known β-strand–turn−β-strand
U-turn motifs. Whereas filaments seeded with 3R tau are structurally
homogeneous, filaments seeded with 4R tau are heterogeneous, composed
of at least three distinct conformers. These findings establish a
molecular basis for the seeding barrier between different tau isoforms
and offer a new powerful approach for investigating the composition
and dynamics of amyloid fibril ensembles.