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- PDB-6iyc: Recognition of the Amyloid Precursor Protein by Human gamma-secretase -

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Entry
Database: PDB / ID: 6iyc
TitleRecognition of the Amyloid Precursor Protein by Human gamma-secretase
Components
  • (Gamma-secretase subunit ...Gamma secretase) x 2
  • Amyloid-beta A4 protein
  • Nicastrin
  • Presenilin-1PSEN1
KeywordsMEMBRANE PROTEIN / Complex
Function / homologyNicastrin small lobe / Presenilin enhancer-2 subunit of gamma secretase / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Kunitz/Bovine pancreatic trypsin inhibitor domain / Presenilin / Amyloid A4 N-terminal heparin-binding / Beta-amyloid peptide (beta-APP) / Nicastrin / Aph-1 protein / Beta-amyloid precursor protein C-terminus ...Nicastrin small lobe / Presenilin enhancer-2 subunit of gamma secretase / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Kunitz/Bovine pancreatic trypsin inhibitor domain / Presenilin / Amyloid A4 N-terminal heparin-binding / Beta-amyloid peptide (beta-APP) / Nicastrin / Aph-1 protein / Beta-amyloid precursor protein C-terminus / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / E2 domain of amyloid precursor protein / Pancreatic trypsin inhibitor (Kunitz) family signature. / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloid precursor protein (APP) intracellular domain signature. / Pancreatic trypsin inhibitor (Kunitz) family profile. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Nuclear signaling by ERBB4 / PH-like domain superfamily / Pancreatic trypsin inhibitor Kunitz domain / Presenilin/signal peptide peptidase / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein / Nicastrin / Gamma-secretase subunit Aph-1 / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, amyloid-beta peptide / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, extracellular domain conserved site / Amyloidogenic glycoprotein, intracellular domain, conserved site / Proteinase inhibitor I2, Kunitz, conserved site / Amyloidogenic glycoprotein, E2 domain / Amyloid-beta precursor protein / Peptidase A22A, presenilin 1 / Platelet degranulation / Degradation of the extracellular matrix / Formyl peptide receptors bind formyl peptides and many other ligands / Amyloid fiber formation / TRAF6 mediated NF-kB activation / Noncanonical activation of NOTCH3 / NOTCH4 Activation and Transmission of Signal to the Nucleus / NOTCH3 Activation and Transmission of Signal to the Nucleus / Post-translational protein phosphorylation / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / Regulated proteolysis of p75NTR / Neutrophil degranulation / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Peptidase A22A, presenilin / Lysosome Vesicle Biogenesis / EPH-ephrin mediated repulsion of cells / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / NOTCH2 Activation and Transmission of Signal to the Nucleus / G alpha (i) signalling events / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / ECM proteoglycans / G alpha (q) signalling events / positive regulation of L-glutamate import across plasma membrane / Cajal-Retzius cell differentiation / positive regulation of coagulation / regulation of resting membrane potential / amyloid precursor protein catabolic process / aspartic endopeptidase activity, intramembrane cleaving / Notch receptor processing, ligand-dependent / gamma-secretase complex / negative regulation of core promoter binding / 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 / regulation of phosphorylation / endoplasmic reticulum calcium ion homeostasis / myeloid dendritic cell differentiation / nuclear outer membrane / positive regulation of receptor recycling / regulation of canonical Wnt signaling pathway / amyloid-beta complex / amylin binding / regulation of acetylcholine-gated cation channel activity
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / single 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 Report
SummaryFull reportAbout validation report
DateDeposition: Dec 14, 2018 / Release: Jan 23, 2019

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Assembly

Deposited unit
A: Nicastrin
B: Presenilin-1
C: Gamma-secretase subunit APH-1A
D: Gamma-secretase subunit PEN-2
E: Amyloid-beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,37931
Polyers184,1175
Non-polymers7,26226
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)23780
ΔGint (kcal/M)-90
Surface area (Å2)61300

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Components

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Protein/peptide , 3 types, 3 molecules ABE

#1: Protein/peptide Nicastrin /


Mass: 78483.570 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / Production host: Homo sapiens (human) / References: UniProt: Q92542
#2: Protein/peptide Presenilin-1 / PSEN1 / PS-1 / Protein S182


Mass: 52688.551 Da / Num. of mol.: 1 / Mutation: Q112C / Source: (gene. exp.) Homo sapiens (human) / Gene: PSEN1, AD3, PS1, PSNL1 / Production host: Homo sapiens (human)
References: UniProt: P49768, Hydrolases, Acting on peptide bonds (peptidases), Aspartic endopeptidases
#5: Protein/peptide Amyloid-beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta precursor protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 11888.622 Da / Num. of mol.: 1 / Fragment: C83 / Mutation: V8C / Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Homo sapiens (human) / References: UniProt: P05067

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

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


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


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

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Non-polymers , 4 types, 26 molecules

#6: Chemical
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 18 / Formula: C8H15NO6 / N-Acetylglucosamine
#7: Chemical ChemComp-BMA / BETA-D-MANNOSE


Mass: 180.156 Da / Num. of mol.: 3 / Formula: C6H12O6
#8: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


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


Mass: 386.654 Da / Num. of mol.: 3 / Formula: C27H46O / Cholesterol

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: human gamma-secretaseGamma secretase / Type: COMPLEX / Entity ID: 1, 2, 3, 4, 5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)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
MicroscopyMicroscope model: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1.5625 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 502450 / Symmetry type: POINT
Refine LS restraints
Refine IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01111337
ELECTRON MICROSCOPYf_angle_d1.19415496
ELECTRON MICROSCOPYf_dihedral_angle_d7.5446606
ELECTRON MICROSCOPYf_chiral_restr0.0701864
ELECTRON MICROSCOPYf_plane_restr0.0081874

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