9B4M
Filament of Tau in complex with D-TLKIVWS, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
Summary for 9B4M
| Entry DOI | 10.2210/pdb9b4m/pdb |
| Related | 9B4I |
| EMDB information | 44185 |
| Descriptor | Microtubule-associated protein tau (1 entity in total) |
| Functional Keywords | alzheimer's disease, tau, fibril, cryo-em, helix, unknown function, protein fibril |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 10 |
| Total formula weight | 790416.17 |
| Authors | |
| Primary citation | Hou, K.,Ge, P.,Sawaya, M.R.,Dolinsky, J.L.,Yang, Y.,Jiang, Y.X.,Lutter, L.,Boyer, D.R.,Cheng, X.,Pi, J.,Zhang, J.,Lu, J.,Yang, S.,Yu, Z.,Feigon, J.,Eisenberg, D.S. How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism. Biorxiv, 2024 Cited by PubMed Abstract: Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's disease (AD). Previously we found that the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disassembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find assembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases. PubMed: 38585812DOI: 10.1101/2024.03.25.586668 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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