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.
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, USA.
Ayisha
A
Siddiqua
Yin
Y
Luo
Virginia
V
Meyer
Michael A
MA
Swanson
Xiang
X
Yu
Guanghong
G
Wei
Jie
J
Zheng
Gareth R
GR
Eaton
Buyong
B
Ma
Ruth
R
Nussinov
Sandra S
SS
Eaton
Martin
M
Margittai
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D020449:Repetitive Sequences, Amino Acid; D013057:Spectrum Analysis; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D020033:Protein Isoforms; D016875:tau Proteins