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- PDB-6ti6: Mixing Abeta(1-40) and Abeta(1-42) peptides generates unique amyl... -

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Basic information

Entry
Database: PDB / ID: 6ti6
TitleMixing Abeta(1-40) and Abeta(1-42) peptides generates unique amyloid fibrils
Components(Amyloid-beta precursor protein) x 2
KeywordsPROTEIN FIBRIL / amyloid beta peptides Alzheimer's disease solid-state NMR supramolecular assembly
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 Wnt signaling pathway / regulation of synapse structure or activity / 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 Wnt signaling pathway / regulation of synapse structure or activity / 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 / negative regulation of neuron differentiation / intracellular copper ion homeostasis / 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 / response to interleukin-1 / positive regulation of mitotic cell cycle / adult locomotory behavior / axonogenesis / extracellular matrix organization / positive regulation of peptidyl-threonine phosphorylation / platelet alpha granule lumen / trans-Golgi network membrane / dendritic shaft / learning / positive regulation of interleukin-1 beta production / locomotory behavior / positive regulation of long-term synaptic potentiation / central nervous system development / endosome lumen / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / 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)
MethodSOLID-STATE NMR / molecular dynamics
AuthorsCerofolini, L. / Ravera, E. / Bologna, S. / Wiglenda, T. / Boddrich, A. / Purfurst, B. / Benilova, A. / Korsak, M. / Gallo, G. / Rizzo, D. ...Cerofolini, L. / Ravera, E. / Bologna, S. / Wiglenda, T. / Boddrich, A. / Purfurst, B. / Benilova, A. / Korsak, M. / Gallo, G. / Rizzo, D. / Gonnelli, L. / Fragai, M. / De Strooper, B. / Wanker, E.E. / Luchinat, C.
CitationJournal: Chem.Commun.(Camb.) / Year: 2020
Title: Mixing A beta (1-40) and A beta (1-42) peptides generates unique amyloid fibrils.
Authors: Cerofolini, L. / Ravera, E. / Bologna, S. / Wiglenda, T. / Boddrich, A. / Purfurst, B. / Benilova, I. / Korsak, M. / Gallo, G. / Rizzo, D. / Gonnelli, L. / Fragai, M. / De Strooper, B. / ...Authors: Cerofolini, L. / Ravera, E. / Bologna, S. / Wiglenda, T. / Boddrich, A. / Purfurst, B. / Benilova, I. / Korsak, M. / Gallo, G. / Rizzo, D. / Gonnelli, L. / Fragai, M. / De Strooper, B. / Wanker, E.E. / Luchinat, C.
History
DepositionNov 21, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jun 14, 2023Group: Database references / Other / Category: database_2 / pdbx_database_status
Item: _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

Downloads & links

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Assembly

Deposited unit
A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein
C: Amyloid-beta precursor protein
D: Amyloid-beta precursor protein
E: Amyloid-beta precursor protein
F: Amyloid-beta precursor protein
G: Amyloid-beta precursor protein
H: Amyloid-beta precursor protein
I: Amyloid-beta precursor protein
J: Amyloid-beta precursor protein
K: Amyloid-beta precursor protein
L: Amyloid-beta precursor protein
M: Amyloid-beta precursor protein
N: Amyloid-beta precursor protein
O: Amyloid-beta precursor protein
P: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)70,84816
Polymers70,84816
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: scanning transmission electron microscopy, The resulting fibrils appear short and highly associated in flat bundles, which do not disassemble to isolated fibrils upon sonication.
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area41840 Å2
ΔGint-252 kcal/mol
Surface area19260 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)4 / 200Top 4 Structures From Haddock
RepresentativeModel #1lowest energy

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Components

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


Mass: 4335.852 Da / Num. of mol.: 8
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
#2: Protein/peptide
Amyloid-beta precursor protein / APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 ...APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 4520.087 Da / Num. of mol.: 8
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: SOLID-STATE NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111anisotropic22D 15N-13C NCA
121anisotropic22D 15N-13C NCO
131anisotropic23D NCACX
141anisotropic23D NCOCX
151anisotropic23D NCACB
161anisotropic23D N(CO)CACB
171anisotropic23D CANCO
181anisotropic12D 13C 13C SHANGHAI (15-300 ms)
191anisotropic12D 13C-13C PDSD (400, 800 ms)
1101anisotropic12D 13C-15N PAIN (10 ms)
1112anisotropic22D 15N-13C NCA
1122anisotropic12D 13C-13C DARR (100 ms)
1133anisotropic22D 15N-13C NCA
1143anisotropic22D 15N-13C NCO
1153anisotropic12D 13C-13C SHANGHAI (15-300 ms)
1164anisotropic32D 15N-13C hNhhC

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
fiber150 uM [U-100% 13C; U-100% 15N] Amyloid-beta peptide 1-40, 50 uM Amyloid-beta peptide 1-42, 50 mM ammonium acetate, H2OThe fibrils were grown in ammonium acetate buffer and then washed with fresh, cold ultrapure water (Millipore) three times.Unlabelled Ab(1-42)/13C 15N Ab(1-40) (1:1)H2O
fiber270 uM [U-100% 13C; U-100% 15N] Amyloid-beta peptide 1-40, 30 uM Amyloid-beta peptide 1-42, 50 mM ammonium acetate, H2OThe fibrils were grown in ammonium acetate buffer and then washed with fresh, cold ultrapure water (Millipore) three times.Unlabelled Ab(1-42)/13C 15N Ab(1-40) (3:7)H2O
fiber350 uM Amyloid-beta peptide 1-40, 50 uM [U-100% 13C; U-100% 15N] Amyloid-beta peptide 1-42, 50 mM ammonium acetate, H2OThe fibrils were grown in ammonium acetate buffer and then washed with fresh, cold ultrapure water (Millipore) three times.13C 15N Ab(1-42)/Ab(1-40) (1:1)H2O
fiber450 uM [U-100% 13C] Amyloid-beta peptide 1-40, 50 uM [U-100% 15N] Amyloid-beta peptide 1-42, 50 mM ammonium acetate, H2OThe fibrils were grown in ammonium acetate buffer and then washed with fresh, cold ultrapure water (Millipore) three times.15N Ab(1-42)/13C Ab(1-40) (1:1)H2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
50 uMAmyloid-beta peptide 1-40[U-100% 13C; U-100% 15N]1
50 uMAmyloid-beta peptide 1-42natural abundance1
50 mMammonium acetatenatural abundance1
70 uMAmyloid-beta peptide 1-40[U-100% 13C; U-100% 15N]2
30 uMAmyloid-beta peptide 1-42natural abundance2
50 mMammonium acetatenatural abundance2
50 uMAmyloid-beta peptide 1-40natural abundance3
50 uMAmyloid-beta peptide 1-42[U-100% 13C; U-100% 15N]3
50 mMammonium acetatenatural abundance3
50 uMAmyloid-beta peptide 1-40[U-100% 13C]4
50 uMAmyloid-beta peptide 1-42[U-100% 15N]4
50 mMammonium acetatenatural abundance4
Sample conditionsIonic strength: 0 Not defined / Label: conditions_1 / pH: 8.5 / Pressure: 1 atm / Temperature: 283 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE IIBrukerAVANCE II7001
Bruker AVANCE IIIBrukerAVANCE III8502
Bruker AVANCE IIIBrukerAVANCE III8003

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Processing

NMR software
NameVersionDeveloperClassification
TopSpinBruker Biospinprocessing
CARAKeller and Wuthrichchemical shift assignment
HADDOCK2.2Bonvinstructure calculation
MODELLERFiser and Salistructure calculation
RefinementMethod: molecular dynamics / Software ordinal: 3
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: Top 4 Structures From Haddock / Conformers calculated total number: 200 / Conformers submitted total number: 4

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