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- PDB-9b4l: Filament of Tau in complex with D-TLKIVWI, a D-peptide that disag... -

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Basic information

Entry
Database: PDB / ID: 9b4l
TitleFilament of Tau in complex with D-TLKIVWI, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
Components
  • DTH-DLE-DLY-DIL-DVA-DTR-DIL
  • Microtubule-associated protein tau
KeywordsPROTEIN FIBRIL / Alzheimer's disease / Tau / fibril / cryo-EM / helix / UNKNOWN FUNCTION
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 / main axon / axonal transport / tubulin complex / positive regulation of protein localization to synapse / 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 / main axon / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of chromosome organization / regulation of mitochondrial fission / axon development / regulation of long-term synaptic depression / central nervous system neuron development / intracellular distribution of mitochondria / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / negative regulation of mitochondrial membrane potential / dynactin binding / apolipoprotein binding / axolemma / protein polymerization / glial cell projection / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / neurofibrillary tangle assembly / positive regulation of axon extension / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / supramolecular fiber organization / synapse assembly / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / positive regulation of microtubule polymerization / axon cytoplasm / stress granule assembly / phosphatidylinositol binding / regulation of microtubule cytoskeleton organization / nuclear periphery / protein phosphatase 2A binding / positive regulation of superoxide anion generation / cellular response to reactive oxygen species / astrocyte activation / Hsp90 protein binding / microglial cell activation / response to lead ion / cellular response to nerve growth factor stimulus / synapse organization / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / memory / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / 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
Chem-EDT / polypeptide(D) / Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsHou, K. / Ge, P. / Sawaya, M.R. / Eisenberg, D.S.
Funding support United States, 3items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Jul 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau
D: Microtubule-associated protein tau
E: DTH-DLE-DLY-DIL-DVA-DTR-DIL
F: DTH-DLE-DLY-DIL-DVA-DTR-DIL
G: DTH-DLE-DLY-DIL-DVA-DTR-DIL
H: DTH-DLE-DLY-DIL-DVA-DTR-DIL
I: DTH-DLE-DLY-DIL-DVA-DTR-DIL
J: DTH-DLE-DLY-DIL-DVA-DTR-DIL
K: DTH-DLE-DLY-DIL-DVA-DTR-DIL
L: DTH-DLE-DLY-DIL-DVA-DTR-DIL
M: Microtubule-associated protein tau
N: Microtubule-associated protein tau
O: Microtubule-associated protein tau
P: Microtubule-associated protein tau
Q: DTH-DLE-DLY-DIL-DVA-DTR-DIL
R: DTH-DLE-DLY-DIL-DVA-DTR-DIL
S: DTH-DLE-DLY-DIL-DVA-DTR-DIL
T: DTH-DLE-DLY-DIL-DVA-DTR-DIL
U: DTH-DLE-DLY-DIL-DVA-DTR-DIL
V: DTH-DLE-DLY-DIL-DVA-DTR-DIL
W: DTH-DLE-DLY-DIL-DVA-DTR-DIL
X: DTH-DLE-DLY-DIL-DVA-DTR-DIL
Y: Microtubule-associated protein tau
Z: Microtubule-associated protein tau
0: Microtubule-associated protein tau
1: Microtubule-associated protein tau
2: DTH-DLE-DLY-DIL-DVA-DTR-DIL
3: DTH-DLE-DLY-DIL-DVA-DTR-DIL
4: DTH-DLE-DLY-DIL-DVA-DTR-DIL
5: DTH-DLE-DLY-DIL-DVA-DTR-DIL
6: DTH-DLE-DLY-DIL-DVA-DTR-DIL
7: DTH-DLE-DLY-DIL-DVA-DTR-DIL
8: DTH-DLE-DLY-DIL-DVA-DTR-DIL
9: DTH-DLE-DLY-DIL-DVA-DTR-DIL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)971,18342
Polymers969,43036
Non-polymers1,7536
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Microtubule-associated protein tau / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 79041.617 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636
#2: Polypeptide(D) ...
DTH-DLE-DLY-DIL-DVA-DTR-DIL


Mass: 872.106 Da / Num. of mol.: 24 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-EDT / {[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID


Mass: 292.243 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H16N2O8 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Tau PHF - D-TLKIVWI ComplexCOMPLEX#1-#20MULTIPLE SOURCES
2Tau PHFCOMPLEX#11NATURAL
3D-TLKIVWICOMPLEX#21SYNTHETIC
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33synthetic construct (others)32630
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTrisC4H11NO31
2100 mMsodium chlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2SerialEMimage acquisition
4CTFFINDCTF correction
7PHENIXmodel fitting
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.2 ° / Axial rise/subunit: 9.65 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 158000
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 26975 / Symmetry type: HELICAL
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Type: experimental model

IDPDB-IDAccession codeInitial refinement model-IDSource nameDetails
17NRV

7nrv

7NRV1PDB
2D_1000282569OtherFrom related PDB deposition
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0088778
ELECTRON MICROSCOPYf_angle_d0.90611772
ELECTRON MICROSCOPYf_dihedral_angle_d14.6473312
ELECTRON MICROSCOPYf_chiral_restr0.0611356
ELECTRON MICROSCOPYf_plane_restr0.0061440

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