Movie
Controller
Structure viewers
About Yorodumi Papers
+Search query
-Structure paper
| Title | Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 121, Issue 10, Page e2316175121, Year 2024 |
| Publish date | Mar 5, 2024 |
 Authors | Nadia El Mammeri / Aurelio J Dregni / Pu Duan / Mei Hong /  |
| PubMed Abstract | The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that ...The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that this posttranslational modification (PTM) may induce tau aggregation. Tau is also phosphorylated in normal developing brains. To investigate how tau phosphorylation induces amyloid fibrils, here we report the atomic structures of two phosphomimetic full-length tau fibrils assembled without anionic cofactors. We mutated key Ser and Thr residues to Glu in two regions of the protein. One construct contains three Glu mutations at the epitope of the anti-phospho-tau antibody AT8 (AT8-3E tau), whereas the other construct contains four Glu mutations at the epitope of the antibody PHF1 (PHF1-4E tau). Solid-state NMR data show that both phosphomimetic tau mutants form homogeneous fibrils with a single set of chemical shifts. The AT8-3E tau rigid core extends from the R3 repeat to the C terminus, whereas the PHF1-4E tau rigid core spans R2, R3, and R4 repeats. Cryoelectron microscopy data show that AT8-3E tau forms a triangular multi-layered core, whereas PHF1-4E tau forms a triple-stranded core. Interestingly, a construct combining all seven Glu mutations exhibits the same conformation as PHF1-4E tau. Scalar-coupled NMR data additionally reveal the dynamics and shape of the fuzzy coat surrounding the rigid cores. These results demonstrate that specific PTMs induce structurally specific tau aggregates, and the phosphorylation code of tau contains redundancy. |
 External links | Proc Natl Acad Sci U S A / PubMed:38408247 / PubMed Central |
| Methods | EM (helical sym.) |
| Resolution | 2.4 - 2.6 Å |
| Structure data | EMDB-41610, PDB-8ttl: EMDB-41611, PDB-8ttn: |
| Source |
|
 Keywords | PROTEIN FIBRIL / Tau / Amyloid Fibril / Phosphomimetic |
homo sapiens (human)