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- PDB-5v5c: VQIINK, Structure of the amyloid-spine from microtubule associate... -

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Basic information

Entry
Database: PDB / ID: 5v5c
TitleVQIINK, Structure of the amyloid-spine from microtubule associated protein tau Repeat 2
ComponentsMicrotubule-associated protein tauTau protein
KeywordsSTRUCTURAL PROTEIN / Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / lipoprotein particle binding / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / negative regulation of mitochondrial membrane potential / dynactin binding / glial cell projection / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / stress granule assembly / cytoplasmic microtubule organization / regulation of cellular response to heat / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / synapse assembly / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / synapse organization / microglial cell activation / response to lead ion / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / cellular response to reactive oxygen species / SH3 domain binding / neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / protein-macromolecule adaptor activity / single-stranded DNA binding / cell-cell signaling / cellular response to heat / cell body / actin binding / growth cone / protein-folding chaperone binding / double-stranded DNA binding / microtubule binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / neuron projection / nuclear speck / membrane raft / axon / negative regulation of gene expression / dendrite / neuronal cell body / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding
Similarity search - Function
: / Microtubule associated protein, tubulin-binding repeat / Microtubule-associated protein Tau / 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 CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / Resolution: 1.25 Å
AuthorsSeidler, P.M. / Sawaya, M.R. / Rodriguez, J.A. / Eisenberg, D.S. / Cascio, D. / Boyer, D.R.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1F32 NS095661 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01 AG029430 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1 AG054022 United States
CitationJournal: Nat Chem / Year: 2018
Title: Structure-based inhibitors of tau aggregation.
Authors: P M Seidler / D R Boyer / J A Rodriguez / M R Sawaya / D Cascio / K Murray / T Gonen / D S Eisenberg /
Abstract: Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its ...Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.
History
DepositionMar 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jun 6, 2018Group: Data collection / Refinement description / Category: software
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)7151
Polymers7151
Non-polymers00
Water0
1
A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau

A: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)12,86818
Polymers12,86818
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_551x,y,z-41
crystal symmetry operation1_552x,y,z-31
crystal symmetry operation1_553x,y,z-21
crystal symmetry operation1_554x,y,z-11
crystal symmetry operation1_556x,y,z+11
crystal symmetry operation1_557x,y,z+21
crystal symmetry operation1_558x,y,z+31
crystal symmetry operation1_559x,y,z+41
crystal symmetry operation4_551x+1/2,-y+1/2,-z-41
crystal symmetry operation4_552x+1/2,-y+1/2,-z-31
crystal symmetry operation4_553x+1/2,-y+1/2,-z-21
crystal symmetry operation4_554x+1/2,-y+1/2,-z-11
crystal symmetry operation4_555x+1/2,-y+1/2,-z1
crystal symmetry operation4_556x+1/2,-y+1/2,-z+11
crystal symmetry operation4_557x+1/2,-y+1/2,-z+21
crystal symmetry operation4_558x+1/2,-y+1/2,-z+31
crystal symmetry operation4_559x+1/2,-y+1/2,-z+41
Unit cell
Length a, b, c (Å)20.360, 43.220, 4.820
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 714.873 Da / Num. of mol.: 1 / Fragment: Repeat 2 peptide (UNP residues 592-597) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10636*PLUS

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Experimental details

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Experiment

ExperimentMethod: ELECTRON CRYSTALLOGRAPHY
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: electron crystallography

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Sample preparation

ComponentName: VQIINK Tau peptide / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
EM crystal formationTemperature: 291 K
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 3D micro-crystal
VitrificationCryogen name: ETHANE
CrystalDensity Matthews: 1.48 Å3/Da / Density % sol: 17.08 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.29 M lithium nitrate, 24% PEG3350

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Data collection

MicroscopyModel: FEI TECNAI 20
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION
Image recordingElectron dose: 0.1 e/Å2 / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k)
EM diffractionCamera length: 730 mm
EM diffraction shellResolution: 1.25→1.31 Å / Fourier space coverage: 71.6 % / Multiplicity: 2.5 / Num. of structure factors: 106 / Phase residual: 0.1 °
EM diffraction statsDetails: This is a crystallography experiment. Phases were not measured.
Fourier space coverage: 86.8 % / High resolution: 1.25 Å / Num. of intensities measured: 5454 / Num. of structure factors: 1226 / Phase error: 0.1 ° / Phase residual: 0.1 ° / Phase error rejection criteria: 0.1 / Rmerge: 23.9 / Rsym: 23.9
DiffractionMean temperature: 100 K
Diffraction sourceSource: ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251 Å
DetectorType: TVIPS TEMCAM-F416 / Detector: CMOS / Date: Aug 25, 2016
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 1.25→10.18 Å / Num. obs: 1226 / % possible obs: 86.8 % / Observed criterion σ(I): -3 / Redundancy: 4.449 % / Biso Wilson estimate: 5.87 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.239 / Rrim(I) all: 0.265 / Χ2: 0.821 / Net I/σ(I): 3.58 / Num. measured all: 5454 / Scaling rejects: 5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.25-1.312.5190.4751.592671481060.5540.59971.6
1.31-1.373.1710.561.553901531230.66580.4
1.37-1.443.7250.8251.324471521200.94978.9
1.44-1.534.3890.6482.115751551310.360.72584.5
1.53-1.644.7340.3983.086061451280.8920.43788.3
1.64-1.774.3890.4492.64741141080.5530.49894.7
1.77-1.944.9170.3853.285361151090.8080.42394.8
1.94-2.175.540.2975.056261181130.80.32495.8
2.17-2.55.8090.2665.846391101100.9950.291100
2.5-3.064.3940.2255.1631276710.9350.25293.4
3.06-4.335.620.1589.439979710.9780.17589.9
4.33-10.185.0830.1328.7618347360.9950.14276.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
EM software
IDNameVersionCategory
6Coot0.8.2model fitting
8Phasermolecular replacement
10XDSsymmetry determination
11XSCALEcrystallography merging
13BUSTER2.10.0model refinement
EM 3D crystal entity∠α: 90 ° / ∠β: 90 ° / ∠γ: 90 ° / A: 20.36 Å / B: 43.22 Å / C: 4.82 Å / Space group name: P21212 / Space group num: 18
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.25→10.18 Å / Cor.coef. Fo:Fc: 0.9086 / Cor.coef. Fo:Fc free: 0.9428 / SU R Cruickshank DPI: 0.072 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.067 / SU Rfree Blow DPI: 0.074 / SU Rfree Cruickshank DPI: 0.07
RfactorNum. reflection% reflectionSelection details
Rfree0.2664 126 10.28 %RANDOM
Rwork0.2194 ---
obs0.2244 1226 87.14 %-
Displacement parametersBiso max: 49.96 Å2 / Biso mean: 15.3 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-0.3575 Å20 Å20 Å2
2---4.8859 Å20 Å2
3---4.5283 Å2
LS refinement shellResolution: 1.25→1.4 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2471 29 10.47 %
Rwork0.2456 248 -
all0.2458 277 -
obs--87.14 %

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