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- EMDB-9751: Recognition of the Amyloid Precursor Protein by Human gamma-secretase -

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Entry
Database: EMDB / ID: 9751
TitleRecognition of the Amyloid Precursor Protein by Human gamma-secretase
Map data
Samplehuman gamma-secretaseGamma secretase
  • Nicastrin
  • Presenilin-1PSEN1
  • (Gamma-secretase subunit ...Gamma secretase) x 2
  • Amyloid-beta A4 protein
  • (ligand) x 4
Function / homologyAmyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein / Nicastrin / Gamma-secretase subunit Aph-1 / Lysosome Vesicle Biogenesis / Formyl peptide receptors bind formyl peptides and many other ligands / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / PH-like domain superfamily ...Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein / Nicastrin / Gamma-secretase subunit Aph-1 / Lysosome Vesicle Biogenesis / Formyl peptide receptors bind formyl peptides and many other ligands / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / PH-like domain superfamily / Pancreatic trypsin inhibitor Kunitz domain / Neutrophil degranulation / Amyloidogenic glycoprotein, amyloid-beta peptide / Amyloidogenic glycoprotein, heparin-binding / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Beta-amyloid precursor protein C-terminal / The NLRP3 inflammasome / Amyloidogenic glycoprotein, extracellular domain conserved site / Amyloidogenic glycoprotein, intracellular domain, conserved site / Presenilin/signal peptide peptidase / G alpha (i) signalling events / Amyloidogenic glycoprotein, E2 domain / Amyloid precursor protein (APP) E1 domain profile. / Regulated proteolysis of p75NTR / Activated NOTCH1 Transmits Signal to the Nucleus / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Degradation of the extracellular matrix / Nuclear signaling by ERBB4 / Platelet degranulation / Amyloid precursor protein (APP) E2 domain profile. / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Peptidase A22A, presenilin 1 / NOTCH2 Activation and Transmission of Signal to the Nucleus / ECM proteoglycans / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Pancreatic trypsin inhibitor (Kunitz) family profile. / EPH-ephrin mediated repulsion of cells / G alpha (q) signalling events / NRIF signals cell death from the nucleus / Peptidase A22A, presenilin / Proteinase inhibitor I2, Kunitz, conserved site / Amyloid precursor protein (APP) intracellular domain signature. / Advanced glycosylation endproduct receptor signaling / Kunitz/Bovine pancreatic trypsin inhibitor domain / Amyloid fiber formation / Pancreatic trypsin inhibitor (Kunitz) family signature. / E2 domain of amyloid precursor protein / Copper-binding of amyloid precursor, CuBD / Beta-amyloid precursor protein C-terminus / Presenilin enhancer-2 subunit of gamma secretase / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Nicastrin / Beta-amyloid peptide (beta-APP) / Amyloid A4 N-terminal heparin-binding / TRAF6 mediated NF-kB activation / Presenilin / Aph-1 protein / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Post-translational protein phosphorylation / Noncanonical activation of NOTCH3 / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Pancreatic trypsin inhibitor Kunitz domain superfamily / NOTCH3 Activation and Transmission of Signal to the Nucleus / NOTCH4 Activation and Transmission of Signal to the Nucleus / E2 domain superfamily / Amyloidogenic glycoprotein, copper-binding domain superfamily / Amyloid-beta precursor protein / positive regulation of L-glutamate import across plasma membrane / Cajal-Retzius cell differentiation / regulation of resting membrane potential / positive regulation of coagulation / aspartic endopeptidase activity, intramembrane cleaving / amyloid precursor protein catabolic process / Notch receptor processing, ligand-dependent / negative regulation of core promoter binding / gamma-secretase complex / choline transport / synaptic vesicle targeting / Notch receptor processing / neural retina development / T cell activation involved in immune response / epithelial cell proliferation / amyloid-beta formation / dorsal/ventral neural tube patterning / membrane protein intracellular domain proteolysis / brain morphogenesis / amyloid precursor protein metabolic process / skin morphogenesis / metanephros development / negative regulation of epidermal growth factor-activated receptor activity / endoplasmic reticulum calcium ion homeostasis / regulation of phosphorylation / myeloid dendritic cell differentiation / nuclear outer membrane / positive regulation of receptor recycling / regulation of canonical Wnt signaling pathway / amylin binding / regulation of acetylcholine-gated cation channel activity / amyloid-beta complex / positive regulation of G protein-coupled receptor internalization
Function and homology information
SourceHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / 2.6 Å resolution
AuthorsZhou R / Yang G / Guo X / Zhou Q / Lei J / Shi Y
CitationJournal: Science / Year: 2019
Title: Recognition of the amyloid precursor protein by human γ-secretase.
Authors: Rui Zhou / Guanghui Yang / Xuefei Guo / Qiang Zhou / Jianlin Lei / Yigong Shi
Abstract: Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease. We report an atomic structure of human γ-secretase in complex with a ...Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease. We report an atomic structure of human γ-secretase in complex with a transmembrane APP fragment at 2.6-Å resolution. The transmembrane helix (TM) of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β-sheet, which is formed by a β-strand from APP and two β-strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β-strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be exploited toward design of substrate-specific inhibitors.
Validation ReportPDB-ID: 6iyc

SummaryFull reportAbout validation report
DateDeposition: Dec 14, 2018 / Header (metadata) release: Jan 23, 2019 / Map release: Jan 23, 2019 / Last update: Jan 23, 2019

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.024
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6iyc
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_9751.map.gz (map file in CCP4 format, 131073 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
320 pix
1.09 Å/pix.
= 349.12 Å
320 pix
1.09 Å/pix.
= 349.12 Å
320 pix
1.09 Å/pix.
= 349.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density
Contour Level:0.024 (by author), 0.024 (movie #1):
Minimum - Maximum-0.072122596 - 0.1844018
Average (Standard dev.)-0.00004957208 (0.0029892963)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions320320320
Origin0.00.00.0
Limit319.0319.0319.0
Spacing320320320
CellA=B=C: 349.12 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z349.120349.120349.120
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0720.184-0.000

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Supplemental data

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Sample components

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Entire human gamma-secretase

EntireName: human gamma-secretase / Number of components: 10

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Component #1: protein, human gamma-secretase

ProteinName: human gamma-secretaseGamma secretase / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #2: protein, Nicastrin

ProteinName: Nicastrin / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 78.48357 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Presenilin-1

ProteinName: Presenilin-1PSEN1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 52.688551 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #4: protein, Gamma-secretase subunit APH-1A

ProteinName: Gamma-secretase subunit APH-1AGamma secretase / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 29.017943 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, Gamma-secretase subunit PEN-2

ProteinName: Gamma-secretase subunit PEN-2Gamma secretase / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 12.038029 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #6: protein, Amyloid-beta A4 protein

ProteinName: Amyloid-beta A4 protein / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 11.888622 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #7: ligand, N-ACETYL-D-GLUCOSAMINE

LigandName: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine / Number of Copies: 18 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Component #8: ligand, BETA-D-MANNOSE

LigandName: BETA-D-MANNOSE / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 0.180156 kDa

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Component #9: ligand, 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

LigandName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.790145 kDa

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Component #10: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 1.5625 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 502450
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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