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- PDB-8oqz: Structure of human gamma-secretase PSEN1 APH-1B isoform reconstit... -

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Basic information

Entry
Database: PDB / ID: 8oqz
TitleStructure of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc in complex with Ab46
Components
  • (Gamma-secretase subunit ...) x 2
  • Amyloid-beta peptide 1-46
  • Nicastrin
  • Presenilin-1 CTF12
KeywordsMEMBRANE PROTEIN / intramembrane proteolysis / protease / di-aspartyl protease / Alzheimer's disease / complex / amyloid beta
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 / T cell activation involved in immune response / skin morphogenesis / choline transport / 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 / locomotion / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / smooth endoplasmic reticulum calcium ion homeostasis / cell fate specification / astrocyte activation involved in immune response / regulation of canonical Wnt signaling pathway / regulation of postsynapse organization / aggresome / azurophil granule membrane / myeloid cell homeostasis / skeletal system morphogenesis / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / ciliary rootlet / positive regulation of amyloid fibril formation / regulation of neuron projection development / protein glycosylation / positive regulation of receptor recycling / blood vessel development / amyloid-beta formation / mitochondrial transport / heart looping / amyloid precursor protein catabolic process / positive regulation of dendritic spine development / nuclear outer membrane / adult behavior / cerebral cortex cell migration / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / autophagosome assembly / EPH-ephrin mediated repulsion of cells / negative regulation of ubiquitin-dependent protein catabolic process / endopeptidase activator activity / neuron development / T cell proliferation / somitogenesis / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / calcium ion homeostasis / regulation of synaptic transmission, glutamatergic / transport vesicle / rough endoplasmic reticulum / Notch signaling pathway / Degradation of the extracellular matrix / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / cerebellum development / NRIF signals cell death from the nucleus / cellular response to calcium ion / Activated NOTCH1 Transmits Signal to the Nucleus / thymus development / positive regulation of glycolytic process / epithelial cell proliferation / dendritic shaft / post-embryonic development / PDZ domain binding / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / apoptotic signaling pathway / synapse organization / sarcolemma
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
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Presenilin-1 / Gamma-secretase subunit APH-1B / Nicastrin / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsOdorcic, I. / Chavez Gutierrez, L. / Efremov, R.G.
Funding support Belgium, 4items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO)G0H5916N Belgium
Research Foundation - Flanders (FWO)G054617N Belgium
Research Foundation - Flanders (FWO)G0B2519N Belgium
Research Foundation - Flanders (FWO)G008023N Belgium
CitationJournal: Nat Commun / Year: 2024
Title: Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.
Authors: Ivica Odorčić / Mohamed Belal Hamed / Sam Lismont / Lucía Chávez-Gutiérrez / Rouslan G Efremov /
Abstract: Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase ...Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aβ peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer's pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aβ, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate Aβ46 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-Aβ46 structure reveals an interaction between Aβ46 and loop 1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.
History
DepositionApr 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 13, 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

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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-1B
D: Gamma-secretase subunit PEN-2
E: Amyloid-beta peptide 1-46
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,30030
Polymers178,1955
Non-polymers14,10525
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules ABE

#1: Protein Nicastrin


Mass: 79371.586 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): BTI-TN5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q92542
#2: Protein Presenilin-1 CTF12 / PS1-CTF12


Mass: 52669.527 Da / Num. of mol.: 1 / Mutation: D257A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSEN1, AD3, PS1, PSNL1 / Cell line (production host): BTI-TN5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P49768
#5: Protein Amyloid-beta peptide 1-46


Mass: 5634.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Since a sequence register could not be assigned, the provided sequence is a poly-alanine
Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Escherichia coli (E. coli)

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

#3: Protein Gamma-secretase subunit APH-1B / APH-1b / Aph-1beta / Presenilin-stabilization factor-like


Mass: 28480.844 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APH1B, PSFL, UNQ688/PRO1328 / Cell line (production host): BTI-TN5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8WW43
#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 / Cell line (production host): BTI-TN5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NZ42

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Sugars , 2 types, 11 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.: 3
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
#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.: 8 / 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 , 1 types, 14 molecules

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


Mass: 790.145 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM

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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: Gamma secretase / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.172 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper) / Cell: BTI-TN5B1-4
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMPIPESC8H18N2O6S21
2100 mMsodium chlorideNaCl1
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-2/1
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 89 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 60000 X / Nominal defocus max: 2300 nm / Nominal defocus min: 1300 nm / Calibrated defocus min: 1200 nm / Calibrated defocus max: 2800 nm / Cs: 2.55 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: JEOL CRYOSPECPORTER
Image recordingAverage exposure time: 2.8 sec. / Electron dose: 56 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 18855
EM imaging opticsEnergyfilter name: In-column Omega Filter / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
1crYOLO1.7particle selection
2SerialEM3.8.18image acquisition
4CTFFIND4.1.14CTF correction
7Coot0.9.8model fitting
9PHENIX1.19.2model refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
12RELION3.1classification
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2788683
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 53612 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDAccession codeInitial refinement model-IDSource nameTypeChain-ID
16IYC

6iyc

6IYC1PDBexperimental model
2Modellerin silico modelC
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411367
ELECTRON MICROSCOPYf_angle_d0.81915397
ELECTRON MICROSCOPYf_dihedral_angle_d15.9874134
ELECTRON MICROSCOPYf_chiral_restr0.0511775
ELECTRON MICROSCOPYf_plane_restr0.0071849

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