[English] 日本語
Yorodumi- PDB-8oqz: Structure of human gamma-secretase PSEN1 APH-1B isoform reconstit... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8oqz | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Structure of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc in complex with Ab46 | |||||||||||||||
Components |
| |||||||||||||||
Keywords | MEMBRANE 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 / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process / positive regulation of endopeptidase activity / Noncanonical activation of NOTCH3 / sequestering of calcium ion / Notch receptor processing / choline transport / central nervous system myelination / synaptic vesicle targeting / membrane protein intracellular domain proteolysis / negative regulation of axonogenesis / regulation of resting membrane potential / T cell activation involved in immune response / NOTCH4 Activation and Transmission of Signal to the Nucleus / skin morphogenesis / growth factor receptor binding / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / cerebral cortex cell migration / regulation of phosphorylation / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / glutamate receptor signaling pathway / locomotion / amyloid precursor protein metabolic process / regulation of canonical Wnt signaling pathway / smooth endoplasmic reticulum calcium ion homeostasis / aggresome / astrocyte activation involved in immune response / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / skeletal system morphogenesis / cell fate specification / myeloid cell homeostasis / ciliary rootlet / regulation of postsynapse organization / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / positive regulation of amyloid fibril formation / adult behavior / mitochondrial transport / positive regulation of dendritic spine development / positive regulation of receptor recycling / blood vessel development / regulation of neuron projection development / heart looping / protein glycosylation / amyloid precursor protein catabolic process / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / endopeptidase activator activity / autophagosome assembly / EPH-ephrin mediated repulsion of cells / smooth endoplasmic reticulum / neuron development / hematopoietic progenitor cell differentiation / negative regulation of ubiquitin-dependent protein catabolic process / somitogenesis / calcium ion homeostasis / T cell proliferation / Nuclear signaling by ERBB4 / rough endoplasmic reticulum / transport vesicle / epithelial cell proliferation / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / Degradation of the extracellular matrix / positive regulation of glycolytic process / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / post-embryonic development / thymus development / negative regulation of protein phosphorylation / dendritic shaft / PDZ domain binding / apoptotic signaling pathway / cell-cell adhesion / synapse organization Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||||||||
Authors | Odorcic, I. / Chavez Gutierrez, L. / Efremov, R.G. | |||||||||||||||
Funding support | Belgium, 4items
| |||||||||||||||
Citation | Journal: 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 |
|
-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
---|
-Downloads & links
-Download
PDBx/mmCIF format | 8oqz.cif.gz | 266.1 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb8oqz.ent.gz | 208.8 KB | Display | PDB format |
PDBx/mmJSON format | 8oqz.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/oq/8oqz ftp://data.pdbj.org/pub/pdb/validation_reports/oq/8oqz | HTTPS FTP |
---|
-Related structure data
Related structure data | 17113MC 8oqyC M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
-Protein , 3 types, 3 molecules ABE
#1: Protein | 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 | 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 | 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) |
-Gamma-secretase subunit ... , 2 types, 2 molecules CD
#3: Protein | 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 | 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 |
-Sugars , 2 types, 11 molecules
#6: Polysaccharide | Source method: isolated from a genetically manipulated source #7: Sugar | ChemComp-NAG / |
---|
-Non-polymers , 1 types, 14 molecules
#8: Chemical | ChemComp-PC1 / |
---|
-Details
Has ligand of interest | N |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Gamma secretase / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Molecular weight | Value: 0.172 MDa / Experimental value: NO | |||||||||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||
Source (recombinant) | Organism: Trichoplusia ni (cabbage looper) / Cell: BTI-TN5B1-4 | |||||||||||||||
Buffer solution | pH: 7.4 | |||||||||||||||
Buffer component |
| |||||||||||||||
Specimen | Conc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-2/1 | |||||||||||||||
Vitrification | Instrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 89 % / Chamber temperature: 277 K |
-Electron microscopy imaging
Microscopy | Model: JEOL CRYO ARM 300 |
---|---|
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: 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 holder | Cryogen: NITROGEN / Specimen holder model: JEOL CRYOSPECPORTER |
Image recording | Average 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 optics | Energyfilter name: In-column Omega Filter / Energyfilter slit width: 20 eV |
Image scans | Width: 5760 / Height: 4092 |
-Processing
Software | Name: PHENIX / Version: 1.19.2_4158: / Classification: refinement | ||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EM software |
| ||||||||||||||||||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 2788683 | ||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 53612 / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | 3D fitting-ID: 1
| ||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
|