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Title | Disease-associated patterns of acetylation stabilize tau fibril formation. |
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Journal, issue, pages | Structure, Vol. 31, Issue 9, Page 1025-11037.e4, Year 2023 |
Publish date | Sep 7, 2023 |
Authors | Li Li / Binh A Nguyen / Vishruth Mullapudi / Yang Li / Lorena Saelices / Lukasz A Joachimiak / |
PubMed 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 ...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. |
External links | Structure / PubMed:37348495 / PubMed Central |
Methods | EM (helical sym.) |
Resolution | 3.88 Å |
Structure data | EMDB-28721: CryoEM structure of synthetic tau repeat R1R2 with two acetylated lysines at positions 274 and 280 |
Source |
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Keywords | PROTEIN FIBRIL / Amyloid motif acetylation tau repeat domain post-translational modification |