|Entry||Database: PDB / ID: 6iyc|
|Title||Recognition of the Amyloid Precursor Protein by Human gamma-secretase|
|Keywords||MEMBRANE PROTEIN / Complex|
|Function / homology||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 ...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 source||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 2.6 Å resolution|
|Authors||Zhou, R. / Yang, G. / Guo, X. / Zhou, Q. / Lei, J. / Shi, Y.|
|Citation||Journal: 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.
SummaryFull reportAbout validation report
|Date||Deposition: Dec 14, 2018 / Release: Jan 23, 2019|
|Structure viewer||Molecule: |
Downloads & links
C: Gamma-secretase subunit APH-1A
D: Gamma-secretase subunit PEN-2
E: Amyloid-beta A4 protein
-Protein/peptide , 3 types, 3 molecules A
|#1: Protein/peptide|| |
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|| |
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|| |
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
-Gamma-secretase subunit ... , 2 types, 2 molecules C
|#3: Protein/peptide|| |
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|| |
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
-Non-polymers , 4 types, 26 molecules
|#7: Chemical||#8: Chemical||#9: Chemical|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: single particle reconstruction|
|Component||Name: human gamma-secretaseGamma secretase / Type: COMPLEX / Entity ID: 1,||Source (natural)||Organism: Homo sapiens (human)||Source (recombinant)||Organism: Homo sapiens (human)||Buffer solution||pH: 7.4||Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES||Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 1.5625 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.13_2998: / Classification: refinement|
|CTF correction||Type: NONE|
|3D reconstruction||Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 502450 / Symmetry type: POINT|
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