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- PDB-8v1n: Cryo-EM structure of tau filaments made from jR2R3-P301L peptides... -

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Basic information

Entry
Database: PDB / ID: 8v1n
TitleCryo-EM structure of tau filaments made from jR2R3-P301L peptides induced with heparin
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / tau / amyloid / filament / P301L
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 / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / 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 / positive regulation of axon extension / neurofibrillary tangle assembly / 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 / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / 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
Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3 Å
AuthorsVigers, M. / Han, S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM136411 United States
National Institutes of Health/Office of the DirectorU24GM129547 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Water-directed pinning is key to tau prion formation.
Authors: Michael P Vigers / Samuel Lobo / Saeed Najafi / Austin Dubose / Karen Tsay / Pritam Ganguly / Andrew P Longhini / Yingying Jin / Steven K Buratto / Kenneth S Kosik / M Scott Shell / Joan-Emma Shea / Songi Han /
Abstract: Tau forms fibrillar aggregates that are pathological hallmarks of a family of neurodegenerative diseases known as tauopathies. The synthetic replication of disease-specific fibril structures is a ...Tau forms fibrillar aggregates that are pathological hallmarks of a family of neurodegenerative diseases known as tauopathies. The synthetic replication of disease-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical and minimal folding motif in fibrils characteristic of tauopathies and generating seeding-competent fibrils from the isolated tau peptides. The 19-residue jR2R3 peptide (295 to 313) which spans the R2/R3 splice junction of tau, and includes the P301L mutation, is one such peptide that forms prion-competent fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of all known pathological tau fibril structures and an intramolecular counterstrand that stabilizes the strand-loop-strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site to facilitate site-directed pinning and dewetting around sites 300-301 to achieve in-register stacking of tau to cross β-sheets. We solved a 3 Å cryo-EM structure of jR2R3-P301L fibrils in which each protofilament layer contains two jR2R3-P301L copies, of which one adopts a SLS fold found in 4R tauopathies and the other wraps around the SLS fold to stabilize it, reminiscent of the three- and fourfold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are competent to template full-length 4R tau in a prion-like manner.
History
DepositionNov 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 25, 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _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: Microtubule-associated protein tau
F: Microtubule-associated protein tau
G: Microtubule-associated protein tau
H: Microtubule-associated protein tau
I: Microtubule-associated protein tau
J: Microtubule-associated protein tau
K: Microtubule-associated protein tau
L: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)24,31612
Polymers24,31612
Non-polymers00
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/peptide
Microtubule-associated protein tau / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 2026.359 Da / Num. of mol.: 12 / Mutation: P618L / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10636
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

ComponentName: Filament of tau jR2R3-P301L peptide indued with heparin
Type: CELL / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: synthetic construct (others)
Buffer solutionpH: 7.4 / Details: 20mM ammoniium acetate, 50mM NaCl
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMsodium chlorideNaCl1
220 mMammonium acetateNH4COOH1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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 defocus max: 2000 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.129 sec. / Electron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1

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Processing

EM software
IDNameVersionCategoryDetails
1RELION4particle selectionfilaments were selected manually
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.43 ° / Axial rise/subunit: 2.39 Å / Axial symmetry: C1
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85235 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL
RefinementCross valid method: NONE

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