Disease-associated patterns of acetylation stabilize tau fibril formation.
Structure
; 31(9): 1025-1037.e4, 2023 09 07.
Article
in En
| MEDLINE
| ID: mdl-37348495
ABSTRACT
Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has emerged. Using tau fragments, we identify patterns of acetylation that flank amyloidogenic motifs on the tau fragments that promote rapid fibril assembly. We determined a 3.9 Å cryo-EM amyloid fibril structure assembled from an acetylated tau fragment uncovering how lysine acetylation can mediate gain-of-function interactions. Comparison of the structure to an ex vivo tauopathy fibril reveals regions of structural similarity. Finally, we show that fibrils encoding disease-associated patterns of acetylation are active in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting tau aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct amyloid folds.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Protein Processing, Post-Translational
/
Tauopathies
/
Amyloid
/
Lysine
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Year:
2023
Type:
Article