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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 tau
KeywordsSTRUCTURAL PROTEIN / Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT
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 / axonal transport / positive regulation of protein localization to synapse / main axon / phosphatidylinositol bisphosphate binding / regulation of long-term synaptic depression ...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 / axonal transport / positive regulation of protein localization to synapse / main axon / phosphatidylinositol bisphosphate binding / regulation of long-term synaptic depression / tubulin complex / 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 / 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 / dynactin binding / negative regulation of mitochondrial membrane potential / apolipoprotein binding / glial cell projection / 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 / Activation of AMPK downstream of NMDARs / synapse assembly / regulation of cellular response to heat / supramolecular fiber organization / positive regulation of protein localization / regulation of calcium-mediated signaling / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / cytoplasmic microtubule organization / axon cytoplasm / positive regulation of microtubule polymerization / 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 / cellular response to nerve growth factor stimulus / response to lead ion / 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 / microtubule binding / protein-macromolecule adaptor activity / dendritic spine / sequence-specific DNA binding / microtubule / amyloid fibril formation / 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 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
Water00
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 / 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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