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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 / positive regulation of protein localization to synapse / neurofibrillary tangle / microtubule lateral binding / axonal transport / main axon / phosphatidylinositol bisphosphate binding / tubulin complex ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / positive regulation of protein localization to synapse / neurofibrillary tangle / microtubule lateral binding / axonal transport / main axon / phosphatidylinositol bisphosphate binding / tubulin complex / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / intracellular distribution of mitochondria / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / apolipoprotein binding / axolemma / protein polymerization / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / neurofibrillary tangle assembly / regulation of microtubule cytoskeleton organization / cytoplasmic microtubule organization / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / synapse assembly / positive regulation of protein localization / axon cytoplasm / regulation of calcium-mediated signaling / supramolecular fiber organization / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / stress granule assembly / positive regulation of microtubule polymerization / phosphatidylinositol binding / nuclear periphery / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / cellular response to reactive oxygen species / astrocyte activation / Hsp90 protein binding / microglial cell activation / synapse organization / cellular response to nerve growth factor stimulus / response to lead ion / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / neuron projection development / microtubule cytoskeleton / cell-cell signaling / single-stranded DNA binding / actin binding / protein-folding chaperone binding / cell body / cellular response to heat / growth cone / double-stranded DNA binding / microtubule binding / protein-macromolecule adaptor activity / microtubule / sequence-specific DNA binding / dendritic spine / amyloid fibril formation / learning or memory / neuron projection / nuclear speck / 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
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: bioRxiv / Year: 2024
Title: How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism.
Authors: Ke Hou / Peng Ge / Michael R Sawaya / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / Liisa Lutter / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Shixin Yang / ...Authors: Ke Hou / Peng Ge / Michael R Sawaya / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / Liisa Lutter / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Shixin Yang / Zhiheng Yu / Juli Feigon / David S Eisenberg
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 ...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.
History
DepositionMar 20, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 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)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.4
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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Slices (1/2)
Density Histograms

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

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
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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