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- PDB-7q4b: Type I beta-amyloid 42 Filaments from Human Brain -

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Entry
Database: PDB / ID: 7q4b
TitleType I beta-amyloid 42 Filaments from Human Brain
ComponentsAmyloid-beta precursor protein
KeywordsPROTEIN FIBRIL / amyloid filaments / Abeta42 / human brain / cryo-EM
Function / homology
Function and homology information


amyloid-beta complex / microglia development / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / regulation of synapse structure or activity / axo-dendritic transport ...amyloid-beta complex / microglia development / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / regulation of synapse structure or activity / axo-dendritic transport / axon midline choice point recognition / astrocyte activation involved in immune response / smooth endoplasmic reticulum calcium ion homeostasis / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / 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 / positive regulation of protein metabolic process / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / signaling receptor activator activity / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / regulation of presynapse assembly / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / forebrain development / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / Notch signaling pathway / clathrin-coated pit / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / axonogenesis / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / response to interleukin-1 / positive regulation of calcium-mediated signaling / cholesterol metabolic process / protein serine/threonine kinase binding / platelet alpha granule lumen / positive regulation of glycolytic process / adult locomotory behavior / dendritic shaft / central nervous system development / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / endosome lumen / learning / locomotory behavior / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / microglial cell activation / serine-type endopeptidase inhibitor activity / synapse organization / regulation of long-term neuronal synaptic plasticity / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction / visual learning / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / endocytosis / positive regulation of inflammatory response / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / 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 / Platelet degranulation / cell-cell junction
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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsYang, Y. / Arseni, D. / Zhang, W. / Huang, M. / Lovestam, S.K.A. / Schweighauser, M. / Kotecha, A. / Murzin, A.G. / Peak-Chew, S.Y. / Macdonald, J. ...Yang, Y. / Arseni, D. / Zhang, W. / Huang, M. / Lovestam, S.K.A. / Schweighauser, M. / Kotecha, A. / Murzin, A.G. / Peak-Chew, S.Y. / Macdonald, J. / Lavenir, I. / Garringer, H.J. / Gelpi, E. / Newell, K.L. / Kovacs, G.G. / Vidal, R. / Ghetti, B. / Falcon, B. / Scheres, S.H.W. / Goedert, M.
Funding support United Kingdom, 6items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
National Institutes of Health/National Institute on Aging (NIH/NIA)P30-AG010133 United Kingdom
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)U01-NS110437 United Kingdom
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1-AG071177 United Kingdom
CitationJournal: Science / Year: 2022
Title: Cryo-EM structures of amyloid-β 42 filaments from human brains.
Authors: Yang Yang / Diana Arseni / Wenjuan Zhang / Melissa Huang / Sofia Lövestam / Manuel Schweighauser / Abhay Kotecha / Alexey G Murzin / Sew Y Peak-Chew / Jennifer Macdonald / Isabelle Lavenir ...Authors: Yang Yang / Diana Arseni / Wenjuan Zhang / Melissa Huang / Sofia Lövestam / Manuel Schweighauser / Abhay Kotecha / Alexey G Murzin / Sew Y Peak-Chew / Jennifer Macdonald / Isabelle Lavenir / Holly J Garringer / Ellen Gelpi / Kathy L Newell / Gabor G Kovacs / Ruben Vidal / Bernardino Ghetti / Benjamin Ryskeldi-Falcon / Sjors H W Scheres / Michel Goedert /
Abstract: Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 ...Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.
History
DepositionOct 30, 2021Deposition site: PDBE / Processing site: PDBE
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Assembly

Deposited unit
R: Amyloid-beta precursor protein
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


Theoretical massNumber of molelcules
Total (without water)45,20120
Polymers45,20110
Non-polymers010
Water1,08160
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area25420 Å2
ΔGint-158 kcal/mol
Surface area12640 Å2

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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: 4520.087 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P05067
#2: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 10 / Source method: obtained synthetically / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: beta-amyloid 42 filaments extracted from the human brain with Alzheimer's disease
Type: TISSUE / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 178.4 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59961 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.012550
ELECTRON MICROSCOPYf_angle_d0.693430
ELECTRON MICROSCOPYf_dihedral_angle_d12.279350
ELECTRON MICROSCOPYf_chiral_restr0.068390
ELECTRON MICROSCOPYf_plane_restr0.002440

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