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- PDB-5v5b: KVQIINKKLD, Structure of the amyloid spine from microtubule assoc... -

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Basic information

Entry
Database: PDB / ID: 5v5b
TitleKVQIINKKLD, 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 / cytoplasmic microtubule organization / regulation of microtubule cytoskeleton organization / stress granule assembly / 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 / microtubule cytoskeleton organization / memory / SH3 domain binding / cellular response to reactive oxygen species / 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 / neuronal cell body / dendrite / 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: 1.5 Å
AuthorsSeidler, P.M. / Sawaya, M.R. / Rodriguez, J.A. / Eisenberg, D.S. / Cascio, D. / Boyer, D.R.
Funding support United States, 4items
OrganizationGrant numberCountry
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
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1F32 NS095661 United States
BrightFocus FoundationA2016588F 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 13, 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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Assembly

Deposited unit
A: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)1,2011
Polymers1,2011
Non-polymers00
Water362
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)21,62718
Polymers21,62718
Non-polymers00
Water32418
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_515x,y-4,z1
crystal symmetry operation1_525x,y-3,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation1_585x,y+3,z1
crystal symmetry operation1_595x,y+4,z1
crystal symmetry operation2_515-x,y-7/2,-z1
crystal symmetry operation2_525-x,y-5/2,-z1
crystal symmetry operation2_535-x,y-3/2,-z1
crystal symmetry operation2_545-x,y-1/2,-z1
crystal symmetry operation2_555-x,y+1/2,-z1
crystal symmetry operation2_565-x,y+3/2,-z1
crystal symmetry operation2_575-x,y+5/2,-z1
crystal symmetry operation2_585-x,y+7/2,-z1
crystal symmetry operation2_595-x,y+9/2,-z1
2
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)21,62718
Polymers21,62718
Non-polymers00
Water32418
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_515x,y-4,z1
crystal symmetry operation1_525x,y-3,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation1_585x,y+3,z1
crystal symmetry operation1_595x,y+4,z1
crystal symmetry operation2_616-x+1,y-7/2,-z+11
crystal symmetry operation2_626-x+1,y-5/2,-z+11
crystal symmetry operation2_636-x+1,y-3/2,-z+11
crystal symmetry operation2_646-x+1,y-1/2,-z+11
crystal symmetry operation2_656-x+1,y+1/2,-z+11
crystal symmetry operation2_666-x+1,y+3/2,-z+11
crystal symmetry operation2_676-x+1,y+5/2,-z+11
crystal symmetry operation2_686-x+1,y+7/2,-z+11
crystal symmetry operation2_696-x+1,y+9/2,-z+11
Unit cell
Length a, b, c (Å)27.120, 4.830, 32.430
Angle α, β, γ (deg.)90.000, 100.530, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 1201.478 Da / Num. of mol.: 1 / Fragment: Repeat 2 peptide (UNP residues 591-600) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10636
#2: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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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: KVQIINKKLD Tau peptide / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 4.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE
CrystalDensity Matthews: 1.74 Å3/Da / Density % sol: 29.23 %
Crystal growTemperature: 310 K / Method: vapor diffusion, hanging drop / pH: 4.2 / Details: 0.1 M phosphate citrate, 32% PEG10000

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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: 1850 mm
EM diffraction shellResolution: 1.5→1.68 Å / Fourier space coverage: 82.4 % / Multiplicity: 6.2 / Num. of structure factors: 370 / Phase residual: 0.1 °
EM diffraction statsDetails: This is a crystallography experiment. / Fourier space coverage: 84.8 % / High resolution: 1.5 Å / Num. of intensities measured: 20047 / Num. of structure factors: 2203 / Phase error: 0 ° / Phase residual: 0.1 ° / Phase error rejection criteria: 0 / Rmerge: 25 / Rsym: 25
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: 1.5→18.83 Å / Num. obs: 2203 / % possible obs: 84.8 % / Observed criterion σ(I): -3 / Redundancy: 9.133 % / Biso Wilson estimate: 8.37 Å2 / CC1/2: 0.984 / Rmerge(I) obs: 0.255 / Rrim(I) all: 0.268 / Χ2: 0.851 / Net I/σ(I): 5.24 / Num. measured all: 20119 / Scaling rejects: 12
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
1.5-1.566.2140.4192.8317463272810.8490.45285.9
1.56-1.637.870.3113.7320622992620.9740.3387.6
1.63-1.717.8350.5053.3115672432000.7280.5482.3
1.71-1.88.2620.5153.1715782291910.6740.5583.4
1.8-1.918.9290.3763.8416342201830.9290.39983.2
1.91-2.0410.170.3065.8920342322000.9590.32186.2
2.04-2.2110.8570.3746.2221282401960.8840.39381.7
2.21-2.4212.3740.2557.5624132281950.9930.26685.5
2.42-2.79.3420.3285.6911211431200.9610.34683.9
2.7-3.129.2070.2866.3911141371210.9740.30388.3
3.12-3.829.9830.2618.7811981331200.9050.27690.2
3.82-5.4112.0280.18611.2412751211060.9860.19387.6
5.41-18.838.8930.1668.424945280.9790.17762.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
BUSTER2.10.0refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
EM software
IDNameVersionCategory
6Coot0.84model fitting
13BUSTER2.10.0model refinement
EM 3D crystal entity∠α: 90 ° / ∠β: 105.53 ° / ∠γ: 90 ° / A: 27.12 Å / B: 4.83 Å / C: 32.43 Å / Space group name: P21 / Space group num: 4
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→18.83 Å / Cor.coef. Fo:Fc: 0.9379 / Cor.coef. Fo:Fc free: 0.9214 / SU R Cruickshank DPI: 0.126 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.1 / SU Rfree Blow DPI: 0.093 / SU Rfree Cruickshank DPI: 0.089
RfactorNum. reflection% reflectionSelection details
Rfree0.2127 132 10.05 %RANDOM
Rwork0.1904 ---
obs0.1927 1313 82.37 %-
Displacement parametersBiso max: 66.55 Å2 / Biso mean: 16.92 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--5.1394 Å20 Å23.5054 Å2
2--4.6904 Å20 Å2
3---0.4491 Å2
Refine analyzeLuzzati coordinate error obs: 0.214 Å
Refinement stepCycle: final / Resolution: 1.5→18.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms81 0 0 2 83
Biso mean---28.48 -
Num. residues----10
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
ELECTRON CRYSTALLOGRAPHYt_dihedral_angle_d51SINUSOIDAL2
ELECTRON CRYSTALLOGRAPHYt_trig_c_planes3HARMONIC2
ELECTRON CRYSTALLOGRAPHYt_gen_planes23HARMONIC5
ELECTRON CRYSTALLOGRAPHYt_it197HARMONIC20
ELECTRON CRYSTALLOGRAPHYt_nbd
ELECTRON CRYSTALLOGRAPHYt_improper_torsion
ELECTRON CRYSTALLOGRAPHYt_pseud_angle
ELECTRON CRYSTALLOGRAPHYt_chiral_improper_torsion13SEMIHARMONIC5
ELECTRON CRYSTALLOGRAPHYt_sum_occupancies
ELECTRON CRYSTALLOGRAPHYt_utility_distance
ELECTRON CRYSTALLOGRAPHYt_utility_angle
ELECTRON CRYSTALLOGRAPHYt_utility_torsion
ELECTRON CRYSTALLOGRAPHYt_ideal_dist_contact141SEMIHARMONIC4
ELECTRON CRYSTALLOGRAPHYt_bond_d197HARMONIC20.01
ELECTRON CRYSTALLOGRAPHYt_angle_deg370HARMONIC21.51
ELECTRON CRYSTALLOGRAPHYt_omega_torsion4.31
ELECTRON CRYSTALLOGRAPHYt_other_torsion11.91
LS refinement shellResolution: 1.5→1.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2097 37 10 %
Rwork0.1871 333 -
all0.1897 370 -
obs--82.37 %

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