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- PDB-6rhy: Structure of pore-forming amyloid-beta tetramers -

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Basic information

Entry
Database: PDB / ID: 6rhy
TitleStructure of pore-forming amyloid-beta tetramers
ComponentsAmyloid beta A4 protein
KeywordsPROTEIN FIBRIL / AMYLOID / Alzheimer's disease / membrane pore / oligomer
Function / homology
Function and homology information


amyloid-beta complex / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport ...amyloid-beta complex / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / mating behavior / regulation of spontaneous synaptic transmission / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / signaling receptor activator activity / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / positive regulation of protein metabolic process / neuromuscular process controlling balance / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / regulation of presynapse assembly / transition metal ion binding / intracellular copper ion homeostasis / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / forebrain development / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / protein serine/threonine kinase binding / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / response to interleukin-1 / positive regulation of mitotic cell cycle / ionotropic glutamate receptor signaling pathway / cholesterol metabolic process / positive regulation of calcium-mediated signaling / axonogenesis / dendritic shaft / platelet alpha granule lumen / adult locomotory behavior / positive regulation of glycolytic process / central nervous system development / learning / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / regulation of long-term neuronal synaptic plasticity / serine-type endopeptidase inhibitor activity / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / neuromuscular junction / visual learning / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / positive regulation of inflammatory response / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / endocytosis / cellular response to amyloid-beta / neuron projection development / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / apical part of cell / synaptic vesicle / cell-cell junction / Platelet degranulation
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / simulated annealing
AuthorsBardiaux, B. / Ciudad, S. / Carulla, N.
Citation
Journal: Nat Commun / Year: 2020
Title: A beta (1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage.
Authors: Ciudad, S. / Puig, E. / Botzanowski, T. / Meigooni, M. / Arango, A.S. / Do, J. / Mayzel, M. / Bayoumi, M. / Chaignepain, S. / Maglia, G. / Cianferani, S. / Orekhov, V. / Tajkhorshid, E. / ...Authors: Ciudad, S. / Puig, E. / Botzanowski, T. / Meigooni, M. / Arango, A.S. / Do, J. / Mayzel, M. / Bayoumi, M. / Chaignepain, S. / Maglia, G. / Cianferani, S. / Orekhov, V. / Tajkhorshid, E. / Bardiaux, B. / Carulla, N.
#1: Journal: Biorxiv / Year: 2019
Title: Abeta(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage
Authors: Ciudad, S. / Puig, E. / Botzanowski, T. / Meigooni, M. / Arango, A.S. / Do, J. / Mayzel, M. / Bayoumi, M. / Chaignepain, S. / Maglia, G. / Cianferani, S. / Orekhov, V. / Tajkhorshid, E. / ...Authors: Ciudad, S. / Puig, E. / Botzanowski, T. / Meigooni, M. / Arango, A.S. / Do, J. / Mayzel, M. / Bayoumi, M. / Chaignepain, S. / Maglia, G. / Cianferani, S. / Orekhov, V. / Tajkhorshid, E. / Bardiaux, B. / Carulla, N.
History
DepositionApr 23, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2020Group: Database references / Category: citation / citation_author
Revision 1.2Jun 14, 2023Group: Database references / Other / Category: citation / database_2 / pdbx_database_status
Item: _citation.journal_id_ISSN / _database_2.pdbx_DOI ..._citation.journal_id_ISSN / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_nmr_data
Revision 1.3Jun 19, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 / Item: _database_2.pdbx_DOI

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Amyloid beta A4 protein
B: Amyloid beta A4 protein
C: Amyloid beta A4 protein
D: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)18,0804
Polymers18,0804
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area3940 Å2
ΔGint-21 kcal/mol
Surface area15590 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)15 / 500structures with the lowest energy
RepresentativeModel #1closest to the average

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Components

#1: Protein/peptide
Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor protein / Beta-amyloid ...ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor protein / Beta-amyloid precursor protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 4520.087 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Escherichia coli (E. coli) / References: UniProt: P05067

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
211isotropic12D 1H-15N TROSY
1161isotropic22D 1H-15N TROSY
222isotropic13D HNCA
1172isotropic23D HNCA
132isotropic13D HNCO
142isotropic13D HN(CO)CA
252isotropic13D HN(CA)CB
1182isotropic23D HN(CA)CB
162isotropic13D HN(COCA)CB
172isotropic13D 13C-HMQC-[1H,1H]-NOESY-13C-HMQC
2192isotropic13D 13C-HMQC-[1H,1H]-NOESY-13C-HMQC
183isotropic13D (Hme)Cme([C]CA)CO
193isotropic13D (Hme)Cme([C]CA)NH
1103isotropic13D Hme(Cme[C]CA)NH
1113isotropic13D (H)C-TOCSY-C-TOCSY-(C)H
1124isotropic13D Hm-CmHm NOESY
2204isotropic13D Hm-CmHm NOESY
1134isotropic13D Cm-CmHm NOESY
2214isotropic13D Cm-CmHm NOESY
1144isotropic13D Hm-NH NOESY
2224isotropic13D Hm-NH NOESY
1154isotropic13D Cm-NH NOESY
2234isotropic13D Cm-NH NOESY

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Sample preparation

Details
TypeSolution-IDContentsLabelSolvent system
micelle11 mM [U-15N] Amyloid-beta A4 protein, 10 mM [U-2H] TRIS-d11, 28.5 mM [U-2H] DPC-d38, 90% H2O/10% D2O15N90% H2O/10% D2O
micelle21 mM [U-13C; U-15N; U-2H] Amyloid-beta A4 protein, 10 mM [U-2H] TRIS-d11, 28.5 mM [U-2H] DPC-d38, 90% H2O/10% D2O[U-2H,13C,15N]90% H2O/10% D2O
micelle31 mM [U-2H,13C,15N]-Ile-[13CH3]d1, Ala-[13CH3], Leu/Val-[13CH3]proR Amyloid-beta A4 protein, 10 mM [U-2H] TRIS-d11, 28.5 mM [U-2H] DPC-d38, 90% H2O/10% D2OAILV_190% H2O/10% D2O
micelle41 mM [U-2H,15N]-Ile-[13CH3]d1, Ala-[13CH3], Leu/Val-[13CH3]proR Amyloid-beta A4 protein, 10 mM [U-2H] TRIS-d11, 28.5 mM [U-2H] DPC-d38, 90% H2O/10% D2OAILV_290% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
1 mMAmyloid-beta A4 protein[U-15N]1
10 mMTRIS-d11[U-2H]1
28.5 mMDPC-d38[U-2H]1
1 mMAmyloid-beta A4 protein[U-13C; U-15N; U-2H]2
10 mMTRIS-d11[U-2H]2
28.5 mMDPC-d38[U-2H]2
1 mMAmyloid-beta A4 protein[U-2H,13C,15N]-Ile-[13CH3]d1, Ala-[13CH3], Leu/Val-[13CH3]proR3
10 mMTRIS-d11[U-2H]3
28.5 mMDPC-d38[U-2H]3
1 mMAmyloid-beta A4 protein[U-2H,15N]-Ile-[13CH3]d1, Ala-[13CH3], Leu/Val-[13CH3]proR4
10 mMTRIS-d11[U-2H]4
28.5 mMDPC-d38[U-2H]4
Sample conditions
Conditions-IDIonic strength unitsLabelpHPressure (kPa)Temperature (K)
1Not definedlow_ph8.51 atm310.15 K
2Not definedhigh_ph9.51 atm310.15 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE IIIBrukerAVANCE III9001
Bruker AVANCEBrukerAVANCE8002

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Processing

NMR software
NameDeveloperClassification
ARIALinge, O'Donoghue and Nilgesstructure calculation
CNSBrunger, Adams, Clore, Gros, Nilges and Readrefinement
TALOSCornilescu, Delaglio and Baxdata analysis
TopSpinBruker Biospinprocessing
CcpNmr AnalysisCCPNchemical shift assignment
Refinement
MethodSoftware ordinal
simulated annealing2
simulated annealing1
NMR representativeSelection criteria: closest to the average
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 500 / Conformers submitted total number: 15

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