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- EMDB-44181: Filament of D-TLKIVWI, a D-peptide that disaggregates Alzheimer's... -

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Basic information

Entry
Database: EMDB / ID: EMD-44181
TitleFilament of D-TLKIVWI, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
Map data
Sample
  • Complex: D-peptide TLKIVWI
    • Protein or peptide: DTH-DLE-DLY-DIL-DVA-DTR-DIL
KeywordsAlzheimer's disease / Tau / fibril / cryo-EM / helix / UNKNOWN FUNCTION
Biological speciessynthetic construct (others)
Methodhelical reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsHou K / Ge P / Sawaya MR / Eisenberg DS
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01AG070895 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1AG065407 United States
Department of Energy (DOE, United States)DOE-FC02-02ERG United States
CitationJournal: Nature / Year: 2025
Title: How short peptides disassemble tau fibrils in Alzheimer's disease.
Authors: Ke Hou / Peng Ge / Michael R Sawaya / Liisa Lutter / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Romany Abskharon / ...Authors: Ke Hou / Peng Ge / Michael R Sawaya / Liisa Lutter / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Romany Abskharon / Shixin Yang / Zhiheng Yu / Juli Feigon / David S Eisenberg /
Abstract: Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD). Previously, we found that in vitro, the D-enantiomeric peptide (D- ...Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD). Previously, we found that in vitro, the D-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like ('mock-amyloid') fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.
History
DepositionMar 20, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44181.png

Downloads & links

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Map

FileDownload / File: emd_44181.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesX (Sec.)Y (Row.)Z (Col.)
0.94 Å/pix.
x 320 pix.
= 300.8 Å		0.94 Å/pix.
x 320 pix.
= 300.8 Å		0.94 Å/pix.
x 320 pix.
= 300.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.21
Minimum - Maximum-15.688663500000001 - 26.093755999999999
Average (Standard dev.)0.00000000000042 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 300.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44181_msk_1.map
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Half map: #2

Fileemd_44181_half_map_1.map
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Half map: #1

Fileemd_44181_half_map_2.map
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Sample components

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Entire : D-peptide TLKIVWI

EntireName: D-peptide TLKIVWI
Components
  • Complex: D-peptide TLKIVWI
    • Protein or peptide: DTH-DLE-DLY-DIL-DVA-DTR-DIL

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Supramolecule #1: D-peptide TLKIVWI

SupramoleculeName: D-peptide TLKIVWI / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: synthetic construct (others) / Synthetically produced: Yes

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Macromolecule #1: DTH-DLE-DLY-DIL-DVA-DTR-DIL

MacromoleculeName: DTH-DLE-DLY-DIL-DVA-DTR-DIL / type: protein_or_peptide / ID: 1 / Number of copies: 60 / Enantiomer: DEXTRO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 872.106 Da
SequenceString:
(DTH)(DLE)(DLY)(DIL)(DVA)(DTR)(DIL)

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration4 mg/mL
BufferpH: 9.07 / Details: Dissolved in de-ionized water
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.8 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 9.659 Å
Applied symmetry - Helical parameters - Δ&Phi: 1.604 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 26250
CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Segment selectionNumber selected: 825000 / Software - Name: crYOLO
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9b4i:
Filament of D-TLKIVWI, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM

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