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- PDB-6idf: Cryo-EM structure of gamma secretase in complex with a Notch fragment -

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Entry
Database: PDB / ID: 6idf
TitleCryo-EM structure of gamma secretase in complex with a Notch fragment
Components
  • (Gamma-secretase subunit ...) x 2
  • Nicastrin
  • Notch1
  • Presenilin-1
KeywordsMEMBRANE PROTEIN / complex
Function / homology
Function and homology information


Defective LFNG causes SCDO3 / coronary sinus valve morphogenesis / cardiac right atrium morphogenesis / cardiac right ventricle formation / growth involved in heart morphogenesis / Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation / cell differentiation in spinal cord / venous endothelial cell differentiation / retinal cone cell differentiation / arterial endothelial cell differentiation ...Defective LFNG causes SCDO3 / coronary sinus valve morphogenesis / cardiac right atrium morphogenesis / cardiac right ventricle formation / growth involved in heart morphogenesis / Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation / cell differentiation in spinal cord / venous endothelial cell differentiation / retinal cone cell differentiation / arterial endothelial cell differentiation / epithelial cell fate commitment / negative regulation of pro-B cell differentiation / Pre-NOTCH Processing in the Endoplasmic Reticulum / negative regulation of inner ear auditory receptor cell differentiation / mitral valve formation / cell migration involved in endocardial cushion formation / negative regulation of photoreceptor cell differentiation / negative regulation of cell proliferation involved in heart valve morphogenesis / regulation of somitogenesis / endocardium morphogenesis / foregut morphogenesis / regulation of cell adhesion involved in heart morphogenesis / distal tubule development / inhibition of neuroepithelial cell differentiation / MAML1-RBP-Jkappa- ICN1 complex / regulation of epithelial cell proliferation involved in prostate gland development / cardiac chamber formation / auditory receptor cell fate commitment / positive regulation of aorta morphogenesis / negative regulation of endothelial cell chemotaxis / atrioventricular node development / positive regulation of transcription of Notch receptor target / neuroendocrine cell differentiation / negative regulation of extracellular matrix constituent secretion / Cajal-Retzius cell differentiation / cellular response to tumor cell / positive regulation of L-glutamate import across plasma membrane / collecting duct development / compartment pattern specification / amyloid precursor protein biosynthetic process / positive regulation of apoptotic process involved in morphogenesis / negative regulation of core promoter binding / positive regulation of endopeptidase activity / vasculogenesis involved in coronary vascular morphogenesis / gamma-secretase complex / regulation of extracellular matrix assembly / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / T-helper 17 type immune response / endocardial cell differentiation / chemical synaptic transmission, postsynaptic / epithelial to mesenchymal transition involved in endocardial cushion formation / positive regulation of amyloid precursor protein biosynthetic process / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / cardiac ventricle morphogenesis / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / positive regulation of smooth muscle cell differentiation / mesenchymal cell development / epidermal cell fate specification / glomerular mesangial cell development / TGFBR3 PTM regulation / negative regulation of myotube differentiation / coronary vein morphogenesis / cardiac left ventricle morphogenesis / sequestering of calcium ion / cardiac vascular smooth muscle cell development / Notch receptor processing / left/right axis specification / synaptic vesicle targeting / positive regulation of coagulation / negative regulation of axonogenesis / somatic stem cell division / central nervous system myelination / negative regulation of cell adhesion molecule production / tissue regeneration / negative regulation of catalytic activity / membrane protein intracellular domain proteolysis / interleukin-17-mediated signaling pathway / endocardium development / apoptotic process involved in embryonic digit morphogenesis / positive regulation of endothelial cell differentiation / positive regulation of cardiac epithelial to mesenchymal transition / growth factor receptor binding / Pre-NOTCH Processing in Golgi / cardiac epithelial to mesenchymal transition / negative regulation of collagen biosynthetic process / pericardium morphogenesis / T cell activation involved in immune response / cardiac atrium morphogenesis / skin morphogenesis / choline transport / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / negative regulation of cardiac muscle hypertrophy / cellular response to follicle-stimulating hormone stimulus / negative regulation of calcium ion-dependent exocytosis / cardiac muscle cell myoblast differentiation / neuronal stem cell population maintenance / NOTCH4 Activation and Transmission of Signal to the Nucleus / calcium-ion regulated exocytosis
Similarity search - Function
Neurogenic locus notch homolog protein 1 / Notch, C-terminal / Domain of unknown function / : / Notch / 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 ...Neurogenic locus notch homolog protein 1 / Notch, C-terminal / Domain of unknown function / : / Notch / 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 / Notch, NOD domain / Notch, NODP domain / NOTCH protein / NOTCH protein / NOD / NODP / 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 / Notch-like domain superfamily / LNR domain / LNR (Lin-12/Notch) repeat profile. / Notch domain / Domain found in Notch and Lin-12 / EGF-like, conserved site / Human growth factor-like EGF / : / Calcium-binding EGF domain / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / Ankyrin repeat / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily
Similarity search - Domain/homology
CHOLESTEROL / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Neurogenic locus notch homolog protein 1 / 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: 2.7 Å
AuthorsYang, G. / Zhou, R. / Zhou, Q. / Guo, X. / Yan, C. / Ke, M. / Lei, J. / Shi, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China31621092 China
CitationJournal: Nature / Year: 2019
Title: Structural basis of Notch recognition by human γ-secretase.
Authors: Guanghui Yang / Rui Zhou / Qiang Zhou / Xuefei Guo / Chuangye Yan / Meng Ke / Jianlin Lei / Yigong Shi /
Abstract: Aberrant cleavage of Notch by γ-secretase leads to several types of cancer, but how γ-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of ...Aberrant cleavage of Notch by γ-secretase leads to several types of cancer, but how γ-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of human γ-secretase in complex with a Notch fragment at a resolution of 2.7 Å. The transmembrane helix of Notch is surrounded by three transmembrane domains of PS1, and the carboxyl-terminal β-strand of the Notch fragment forms a β-sheet with two substrate-induced β-strands of PS1 on the intracellular side. Formation of the hybrid β-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. These features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by γ-secretase.
History
DepositionSep 9, 2018Deposition site: PDBJ / Processing site: PDBJ
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Structure visualization

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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: Notch1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)195,62324
Polymers186,9435
Non-polymers8,68119
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area26970 Å2
ΔGint-112 kcal/mol
Surface area62150 Å2

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Components

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Protein , 3 types, 3 molecules ABE

#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 / Production host: Homo sapiens (human) / References: UniProt: Q92542
#2: Protein Presenilin-1 / PS-1


Mass: 52644.543 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PS1 / Production host: Homo sapiens (human)
References: UniProt: P49768, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases
#5: Protein Notch1


Mass: 14758.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P46531*PLUS

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

#3: Protein Gamma-secretase subunit APH-1A / APH-1a


Mass: 29017.943 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APH1A / 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: PEN2 / Production host: Homo sapiens (human) / References: UniProt: Q9NZ42

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Sugars , 3 types, 12 molecules

#6: 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: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#7: 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}}}}LINUCSPDB-CARE
#8: 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, 7 molecules

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


Mass: 790.145 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#10: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O

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Details

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: gamma-secretase / Type: COMPLEX / Entity ID: #1-#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
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
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: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 476853 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00511489
ELECTRON MICROSCOPYf_angle_d0.98215687
ELECTRON MICROSCOPYf_dihedral_angle_d8.4326693
ELECTRON MICROSCOPYf_chiral_restr0.0571869
ELECTRON MICROSCOPYf_plane_restr0.0071895

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