Academic Journal
Conformational bifurcation of tau R3-R4 oligomers underlies fibril polymorphism.
| Τίτλος: | Conformational bifurcation of tau R3-R4 oligomers underlies fibril polymorphism. |
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| Συγγραφείς: | Zhang T; School of Physics, Shandong University, Jinan 250100, China., Dai L; School of Physics, Shandong University, Jinan 250100, China., Ma Y; Dongying Science and Technology Innovation Service Center, Dongying 257091, China., Xu S; Institute of Biophysics, Dezhou University, Dezhou 253023, China., Liu X; School of Physics, Shandong University, Jinan 250100, China., Zhao M; School of Physics, Shandong University, Jinan 250100, China., Li W; School of Physics, Shandong University, Jinan 250100, China; Institute of Biophysics, Dezhou University, Dezhou 253023, China., Wang J; Department of Colorectal and Anal Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan 250100, China. Electronic address: wangjiayong120@icloud.com., Liu Y; School of Physics, Shandong University, Jinan 250100, China; Institute of Biophysics, Dezhou University, Dezhou 253023, China. Electronic address: lylyn2011@sdu.edu.cn. |
| Πηγή: | Biophysical journal [Biophys J] 2026 Sep 01; Vol. 125 (17), pp. 4756-4767. Date of Electronic Publication: 2026 Jul 18. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Cell Press Country of Publication: United States NLM ID: 0370626 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1542-0086 (Electronic) Linking ISSN: 00063495 NLM ISO Abbreviation: Biophys J Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge, MA : Cell Press Original Publication: New York, Published by Rockefeller University Press [etc.] for the Biophysical Society. |
| Ιατρικοί όροι (MeSH): | tau Proteins*/chemistry , tau Proteins*/metabolism , Amyloid*/chemistry , Amyloid*/metabolism , Protein Multimerization* , Protein Aggregates*, Molecular Dynamics Simulation ; Protein Folding ; Protein Conformation ; Thermodynamics ; Amino Acid Sequence ; Hydrophobic and Hydrophilic Interactions |
| Περίληψη: | Tau aggregation into amyloid fibrils is a central pathological feature of multiple neurodegenerative diseases, yet identical tau sequences can adopt structurally distinct fibril conformations associated with different disorders. How such disease-specific folds emerge from the same sequence remains poorly understood. Here, we use metadynamics and all-atom molecular dynamics simulations to elucidate the folding mechanisms of tau trimers comprising the R3-R4 region, the minimal aggregation nucleus of tau fibrils. By constructing the folding free-energy landscape within a pre-organized fibril-like scaffold, we identify a shared, partially folded intermediate from which two energetically comparable minimum free-energy pathways diverge, leading to either a compact Alzheimer's disease-like or a more open chronic traumatic encephalopathy-like C-shaped conformation. Structural analysis reveals that the β4-β6 triangular region acts as the central determinant of this bifurcation. Hydrophobic-core rearrangements within this region provide the primary energetic driving force for compaction, whereas the conformational flexibility of the (Copyright © 2026 Biophysical Society. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests The authors declare no competing interests. |
| Molecular Sequence: | PDB 5O3L; 6NWP |
| Substance Nomenclature: | 0 (tau Proteins) 0 (Amyloid) 0 (Protein Aggregates) |
| Entry Date(s): | Date Created: 20260719 Date Completed: 20260901 Latest Revision: 20260916 |
| Update Code: | 20260917 |
| DOI: | 10.1016/j.bpj.2026.07.020 |
| PMID: | 42471758 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1542-0086 |
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| DOI: | 10.1016/j.bpj.2026.07.020 |