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- EMDB-44184: Filament of Tau in complex with D-TLKIVWI, a D-peptide that disag... -

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Basic information

Entry
Database: EMDB / ID: EMD-44184
TitleFilament of Tau in complex with D-TLKIVWI, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
Map data
Sample
  • Complex: Tau PHF - D-TLKIVWI Complex
    • Complex: Tau PHF
      • Protein or peptide: Microtubule-associated protein tau
    • Complex: D-TLKIVWI
      • Protein or peptide: DTH-DLE-DLY-DIL-DVA-DTR-DIL
  • Ligand: {[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID
KeywordsAlzheimer's disease / Tau / fibril / cryo-EM / helix / UNKNOWN FUNCTION / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / negative regulation of tubulin deacetylation / phosphatidylinositol bisphosphate binding ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / negative regulation of tubulin deacetylation / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of chromosome organization / central nervous system neuron development / intracellular distribution of mitochondria / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / dynactin binding / regulation of microtubule polymerization / apolipoprotein binding / main axon / protein polymerization / axolemma / glial cell projection / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / neurofibrillary tangle assembly / positive regulation of axon extension / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / synapse assembly / positive regulation of superoxide anion generation / regulation of long-term synaptic depression / positive regulation of protein localization / supramolecular fiber organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / positive regulation of microtubule polymerization / somatodendritic compartment / axon cytoplasm / astrocyte activation / stress granule assembly / phosphatidylinositol binding / nuclear periphery / regulation of microtubule cytoskeleton organization / protein phosphatase 2A binding / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / synapse organization / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / SH3 domain binding / response to lead ion / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / actin binding / microtubule cytoskeleton / cell body / growth cone / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / dendritic spine / sequence-specific DNA binding / amyloid fibril formation / microtubule / learning or memory / neuron projection / regulation of autophagy / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / Tau and MAP protein, tubulin-binding repeat / Tau and MAP proteins tubulin-binding repeat signature. / Tau and MAP proteins tubulin-binding repeat profile. / :
Similarity search - Domain/homology
Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 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-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44184.png

Downloads & links

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Map

FileDownload / File: emd_44184.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesY (Sec.)X (Row.)Z (Col.)
0.94 Å/pix.
x 432 pix.
= 406.08 Å		0.94 Å/pix.
x 432 pix.
= 406.08 Å		0.94 Å/pix.
x 432 pix.
= 406.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.4
Minimum - Maximum-16.358309999999999 - 27.610005999999998
Average (Standard dev.)0.000000014343724 (±1.0000002)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 406.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44184_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_44184_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_44184_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Tau PHF - D-TLKIVWI Complex

EntireName: Tau PHF - D-TLKIVWI Complex
Components
  • Complex: Tau PHF - D-TLKIVWI Complex
    • Complex: Tau PHF
      • Protein or peptide: Microtubule-associated protein tau
    • Complex: D-TLKIVWI
      • Protein or peptide: DTH-DLE-DLY-DIL-DVA-DTR-DIL
  • Ligand: {[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID

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Supramolecule #1: Tau PHF - D-TLKIVWI Complex

SupramoleculeName: Tau PHF - D-TLKIVWI Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: Tau PHF

SupramoleculeName: Tau PHF / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: D-TLKIVWI

SupramoleculeName: D-TLKIVWI / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: synthetic construct (others) / Synthetically produced: Yes

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 79.041617 KDa
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQEPESG KVVQEGFLRE PGPPGLSHQL MSGMPGAPLL P EGPREATR ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQEPESG KVVQEGFLRE PGPPGLSHQL MSGMPGAPLL P EGPREATR QPSGTGPEDT EGGRHAPELL KHQLLGDLHQ EGPPLKGAGG KERPGSKEEV DEDRDVDESS PQDSPPSKAS PA QDGRPPQ TAAREATSIP GFPAEGAIPL PVDFLSKVST EIPASEPDGP SVGRAKGQDA PLEFTFHVEI TPNVQKEQAH SEE HLGRAA FPGAPGEGPE ARGPSLGEDT KEADLPEPSE KQPAAAPRGK PVSRVPQLKA RMVSKSKDGT GSDDKKAKTS TRSS AKTLK NRPCLSPKHP TPGSSDPLIQ PSSPAVCPEP PSSPKYVSSV TSRTGSSGAK EMKLKGADGK TKIATPRGAA PPGQK GQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGSPGTPG SRSRTPSLPT PPTREPKKVA VVRTPPKSPS SAKSRL QTA PVPMPDLKNV KSKIGSTENL KHQPGGGKVQ IINKKLDLSN VQSKCGSKDN IKHVPGGGSV QIVYKPVDLS KVTSKCG SL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTFRENAKAK TDHGAEIVYK SPVVSGDT S PRHLSNVSST GSIDMVDSPQ LATLADEVSA SLAKQGL

UniProtKB: Microtubule-associated protein tau

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Macromolecule #2: DTH-DLE-DLY-DIL-DVA-DTR-DIL

MacromoleculeName: DTH-DLE-DLY-DIL-DVA-DTR-DIL / type: protein_or_peptide / ID: 2 / Number of copies: 24 / 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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Macromolecule #3: {[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID

MacromoleculeName: {[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID
type: ligand / ID: 3 / Number of copies: 6 / Formula: EDT
Molecular weightTheoretical: 292.243 Da
Chemical component information

ChemComp-EDT:
{[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC4H11NO3Tris
100.0 mMNaClsodium chloride
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: 9.65 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.2 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 26975
CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Segment selectionNumber selected: 158000 / 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

Initial model
PDB IDChainDetails

7nrv

source_name: PDB, initial_model_type: experimental model

2569

source_name: Other, initial_model_type: experimental modelFrom related PDB deposition
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9b4l:
Filament of Tau in complex with D-TLKIVWI, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM

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