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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


regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity ...regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / : / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / suckling behavior / nuclear envelope lumen / dendrite development / COPII-coated ER to Golgi transport vesicle / presynaptic active zone / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / intracellular copper ion homeostasis / negative regulation of neuron differentiation / ECM proteoglycans / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / forebrain development / Notch signaling pathway / Mitochondrial protein degradation / neuron projection maintenance / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / positive regulation of mitotic cell cycle / response to interleukin-1 / adult locomotory behavior / extracellular matrix organization / axonogenesis / platelet alpha granule lumen / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / dendritic shaft / learning / positive regulation of interleukin-1 beta production / positive regulation of long-term synaptic potentiation / locomotory behavior / central nervous system development / endosome lumen / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / recycling endosome / cognition / neuron cellular homeostasis / Golgi lumen / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / cellular response to amyloid-beta / G2/M transition of mitotic cell cycle / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle
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. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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 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_ph8.5 1 atm310.15 K
2Not definedhigh_ph9.5 1 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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