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- PDB-8im7: Human gamma-secretase treated with ganglioside GM1 -

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Basic information

Entry
Database: PDB / ID: 8im7
TitleHuman gamma-secretase treated with ganglioside GM1
Components
  • (Gamma-secretase subunit ...) x 2
  • Nicastrin
  • Presenilin-1 CTF12
KeywordsMEMBRANE PROTEIN / intramembrane protease / lipid / ganglioside / GM1
Function / homology
Function and homology information


Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / synaptic vesicle targeting / negative regulation of axonogenesis / positive regulation of coagulation / central nervous system myelination / membrane protein intracellular domain proteolysis / growth factor receptor binding / choline transport / T cell activation involved in immune response / skin morphogenesis / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / neural retina development / regulation of resting membrane potential / L-glutamate import across plasma membrane / regulation of phosphorylation / Regulated proteolysis of p75NTR / myeloid dendritic cell differentiation / metanephros development / brain morphogenesis / locomotion / endoplasmic reticulum calcium ion homeostasis / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / regulation of postsynapse organization / embryonic limb morphogenesis / cell fate specification / astrocyte activation involved in immune response / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / myeloid cell homeostasis / aggresome / azurophil granule membrane / skeletal system morphogenesis / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / Golgi cisterna membrane / ciliary rootlet / positive regulation of amyloid fibril formation / protein glycosylation / blood vessel development / mitochondrial transport / amyloid-beta formation / heart looping / amyloid precursor protein catabolic process / regulation of neuron projection development / positive regulation of dendritic spine development / positive regulation of receptor recycling / cerebral cortex cell migration / nuclear outer membrane / adult behavior / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / EPH-ephrin mediated repulsion of cells / autophagosome assembly / negative regulation of ubiquitin-dependent protein catabolic process / endopeptidase activator activity / neuron development / NOTCH2 Activation and Transmission of Signal to the Nucleus / somitogenesis / T cell proliferation / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / calcium ion homeostasis / NRIF signals cell death from the nucleus / regulation of synaptic transmission, glutamatergic / Activated NOTCH1 Transmits Signal to the Nucleus / rough endoplasmic reticulum / Degradation of the extracellular matrix / Notch signaling pathway / neuron projection maintenance / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / thymus development / cerebellum development / positive regulation of glycolytic process / dendritic shaft / epithelial cell proliferation / post-embryonic development / PDZ domain binding / astrocyte activation / apoptotic signaling pathway / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
Similarity search - Function
Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe ...Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe / Nicastrin large lobe / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family
Similarity search - Domain/homology
CHOLESTEROL / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Presenilin-1 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhou, R. / Yang, G. / Shi, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0509300 China
CitationJournal: Adv Sci (Weinh) / Year: 2023
Title: Preferential Regulation of Γ-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease.
Authors: Xiaotong Wang / Rui Zhou / Xiaqin Sun / Jun Li / Jinxin Wang / Weihua Yue / Lifang Wang / Hesheng Liu / Yigong Shi / Dai Zhang /
Abstract: A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β-amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in ...A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β-amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme-linked immune-sorbent assay (ELISA). Cryo-electron microscopy (Cryo-EM) is used to determine the structure of γ-secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ-secretase structure and specifically accelerates γ-secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N-terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ-secretase activity and the pathogenesis of AD.
History
DepositionMar 6, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
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Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jul 23, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 23, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nicastrin
B: Presenilin-1 CTF12
C: Gamma-secretase subunit APH-1A
D: Gamma-secretase subunit PEN-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,96720
Polymers172,2534
Non-polymers6,71416
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Nicastrin


Mass: 78483.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q92542
#2: Protein Presenilin-1 CTF12 / PS1-CTF12


Mass: 52713.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSEN1, AD3, PS1, PSNL1 / Production host: Homo sapiens (human) / References: UniProt: P49768

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Gamma-secretase subunit ... , 2 types, 2 molecules CD

#3: Protein Gamma-secretase subunit APH-1A / APH-1a / Aph-1alpha / Presenilin-stabilization factor


Mass: 29017.943 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APH1A, PSF, CGI-78, UNQ579/PRO1141 / Production host: Homo sapiens (human) / References: UniProt: Q96BI3
#4: Protein Gamma-secretase subunit PEN-2 / Presenilin enhancer protein 2


Mass: 12038.029 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSENEN, PEN2, MDS033 / Production host: Homo sapiens (human) / References: UniProt: Q9NZ42

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Sugars , 3 types, 12 molecules

#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Polysaccharide beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3[DManpb1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2-2-2/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 4 molecules

#8: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#9: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human gamma-secretase treated with ganglioside GM1 / Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: mono dispersed sample
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 / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.12_2829: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134908 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00911173
ELECTRON MICROSCOPYf_angle_d1.0615274
ELECTRON MICROSCOPYf_dihedral_angle_d7.5116472
ELECTRON MICROSCOPYf_chiral_restr0.0621833
ELECTRON MICROSCOPYf_plane_restr0.0071837

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