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- PDB-9k0f: Cryo-EM structure of Amyloid-beta42-4b polymorph 3 -

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Basic information

Entry
Database: PDB / ID: 9k0f
TitleCryo-EM structure of Amyloid-beta42-4b polymorph 3
Components
  • Amyloid-beta A4 protein
  • Amyloid-beta protein 40
KeywordsMEMBRANE PROTEIN / helical fibril / amyloid-beta / PROTEIN FIBRIL
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity ...amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity / axon midline choice point recognition / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Golgi-associated vesicle / PTB domain binding / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Lysosome Vesicle Biogenesis / astrocyte projection / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / modulation of excitatory postsynaptic potential / The NLRP3 inflammasome / main axon / transition metal ion binding / intracellular copper ion homeostasis / regulation of multicellular organism growth / ECM proteoglycans / regulation of presynapse assembly / positive regulation of T cell migration / neuronal dense core vesicle / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / cellular response to manganese ion / Notch signaling pathway / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / astrocyte activation / ionotropic glutamate receptor signaling pathway / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / axonogenesis / protein serine/threonine kinase binding / response to interleukin-1 / platelet alpha granule lumen / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / endosome lumen / positive regulation of interleukin-1 beta production / dendritic shaft / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / adult locomotory behavior / learning / positive regulation of JNK cascade / Post-translational protein phosphorylation / locomotory behavior / serine-type endopeptidase inhibitor activity / microglial cell activation / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / regulation of long-term neuronal synaptic plasticity / cellular response to nerve growth factor stimulus / recycling endosome / synapse organization / visual learning / response to lead ion / positive regulation of interleukin-6 production / Golgi lumen / cognition / 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 / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / Platelet degranulation / heparin binding / regulation of translation / growth cone / regulation of gene expression / early endosome membrane / G alpha (i) signalling events / perikaryon / G alpha (q) signalling events
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 / Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsXia, W.C. / Sun, Y.P. / Liu, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity.
Authors: Qijia Wei / Dangliang Liu / Wencheng Xia / Fengzhang Wang / Lu Huang / Jun Zhang / Xiaoya Wang / Zhongxin Xu / Changdong He / Wenzhe Li / Xiaomeng Shi / Chu Wang / Yuan Liu / Cong Liu / Suwei Dong /
Abstract: The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into ...The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβ promotes Aβ fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ coassembles with Aβ, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ can alleviate the neurotoxicity of Aβ in neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies.
History
DepositionOct 15, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 6, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Amyloid-beta A4 protein
G: Amyloid-beta A4 protein
I: Amyloid-beta A4 protein
K: Amyloid-beta protein 40
D: Amyloid-beta A4 protein
H: Amyloid-beta A4 protein
L: Amyloid-beta A4 protein
N: Amyloid-beta protein 40
F: Amyloid-beta A4 protein
J: Amyloid-beta A4 protein
M: Amyloid-beta A4 protein
O: Amyloid-beta protein 40


Theoretical massNumber of molelcules
Total (without water)45,41412
Polymers45,41412
Non-polymers00
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein/peptide
Amyloid-beta A4 protein


Mass: 4520.087 Da / Num. of mol.: 9 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: B4DMD5
#2: Protein/peptide Amyloid-beta protein 40 / Abeta40 / Beta-APP40


Mass: 1577.802 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O
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: Cryo-EM structure of Amyloid-beta42-4b polymorph 3 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1-#2 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.15.2_3472: / Category: model refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -0.76 ° / Axial rise/subunit: 4.82 Å / Axial symmetry: C1
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 24373 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0082139
ELECTRON MICROSCOPYf_angle_d0.6892865
ELECTRON MICROSCOPYf_dihedral_angle_d7.6531191
ELECTRON MICROSCOPYf_chiral_restr0.058336
ELECTRON MICROSCOPYf_plane_restr0.002354

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