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.

阿尔茨海默病（Alzheimer’s disease）中的tau蛋白病理，与蛋白质源性细丝的沉积密切相关。这类细丝类似传染性朊病毒（prions），被认为可通过种子化转化机制进行播散。本研究采用双电子-电子共振（double electron–electron resonance, DEER）波谱法结合全面的计算分析，证实3重复（3R）与4重复（4R）tau蛋白的细丝在构象上存在显著差异。通过对第三重复结构域内自旋标记间的距离测量，本研究揭示tau淀粉样细丝为已知β链-转角-β链U形转折基序的集合体。其中，以3R tau为种子诱导形成的细丝结构均一，而以4R tau为种子诱导形成的细丝则具有异质性，至少包含三种不同的构象体。上述发现为不同tau蛋白同工型之间的种子化屏障建立了分子基础，并为探究淀粉样原纤维集合体的组成与动态变化提供了一种全新的有效研究手段。