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- PDB-9mr8: Structure of D421-Truncated Tau Fibril -

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Basic information

Entry
Database: PDB / ID: 9mr8
TitleStructure of D421-Truncated Tau Fibril
ComponentsMicrotubule-associated protein tau
KeywordsSTRUCTURAL PROTEIN / Tau / amyloid fibrils
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of chromosome organization / regulation of microtubule-based movement / 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 / regulation of microtubule polymerization / dynactin binding / 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 / synapse assembly / Activation of AMPK downstream of NMDARs / regulation of long-term synaptic depression / positive regulation of superoxide anion generation / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / somatodendritic compartment / axon cytoplasm / positive regulation of microtubule polymerization / astrocyte activation / phosphatidylinositol binding / enzyme inhibitor activity / nuclear periphery / stress granule assembly / protein phosphatase 2A binding / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / synapse organization / PKR-mediated signaling / regulation of synaptic plasticity / protein homooligomerization / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / regulation of autophagy / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / microtubule cytoskeleton / growth cone / actin binding / cell body / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / sequence-specific DNA binding / dendritic spine / amyloid fibril formation / microtubule / learning or memory / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsEl Mammeri, N. / Duan, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG059661 United States
CitationJournal: J Mol Biol / Year: 2025
Title: Structures of ΔD421 Truncated Tau Fibrils.
Authors: Nadia El Mammeri / Pu Duan / Mei Hong /
Abstract: The microtubule-associated protein tau aggregates into pathological β-sheet amyloid fibrils in Alzheimer's disease (AD) and other neurodegenerative diseases. In these aggregates, tau is chemically ...The microtubule-associated protein tau aggregates into pathological β-sheet amyloid fibrils in Alzheimer's disease (AD) and other neurodegenerative diseases. In these aggregates, tau is chemically modified, including abnormal hyperphosphorylation and truncation. Truncation after D421 in the C-terminal domain occurs at early stages of AD. Here we investigate the structures of ΔD421-truncated 0N4R tau fibrils assembled in vitro in the absence of anionic cofactors. Using solid-state NMR spectroscopy and cryoelectron microscopy, we show that ΔD421-truncated 0N4R tau forms homogeneous fibrils whose rigid core adopts a three-layered β-sheet structure that spans R2, R3 and R4 repeats. This structure is essentially identical to that of full-length tau containing phospho-mimetic mutations at the PHF1 epitope in the C-terminal domain. In comparison, a ΔD421-truncated tau that additionally contains three phospho-mimetic mutations at the AT8 epitope in the proline-rich region forms a fibril core that includes the first half of the C-terminal domain, which is excluded from all known pathological tau fibril cores. These results indicate that the posttranslational modification code of tau contains redundancy: both charge modification and truncation of the C-terminal domain promote a three-layered β-sheet structure, which resembles pathological four-repeat tau structures in several tauopathies. In comparison, reducing the positive charges at the AT8 epitope in ΔD421-truncated tau promotes a fibril core that includes an immobilized C-terminal domain. The absence of this structure in tauopathy brains implies that ΔD421 truncation does not occur in conjunction with AT8 phosphorylation in diseased brains.
History
DepositionJan 7, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)9,6671
Polymers9,6671
Non-polymers00
Water00
1
C: Microtubule-associated protein tau
x 30


Theoretical massNumber of molelcules
Total (without water)290,01330
Polymers290,01330
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
helical symmetry operation29
2


  • Idetical with deposited unit
  • helical asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
SymmetryHelical symmetry: (Circular symmetry: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 30 / Rise per n subunits: 4.768 Å / Rotation per n subunits: -0.93 °)

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Components

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


Mass: 9667.116 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPT, MAPTL, MTBT1, TAU / Production host: Escherichia coli (E. coli) / 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: Tau 0N (1-421) / Type: CELL / Details: tau construct with truncation at D421 / Entity ID: all / Source: NATURAL
Source (natural)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 200 nm
Image recordingElectron dose: 1.04756 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.93 ° / Axial rise/subunit: 4.768 Å / Axial symmetry: C1
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 31533 / Symmetry type: HELICAL
Atomic model buildingProtocol: AB INITIO MODEL

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