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- EMDB-2678: Three-dimensional structure of human gamma-secretase at 5.4 angst... -
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Basic information
Entry | Database: EMDB / ID: EMD-2678 | |||||||||
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Title | Three-dimensional structure of human gamma-secretase at 5.4 angstrom resoltuion | |||||||||
![]() | Reconstruction of human gamma-secretase. The particles were selected by two-steps of 3D classification. This map has good density for the transmembrane domain. All the 19 TM helices and some of the linkers are visible. | |||||||||
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![]() | human gamma-secretase / cryo EM | |||||||||
Function / homology | ![]() Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / protein catabolic process at postsynapse / 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 / positive regulation of amyloid precursor protein biosynthetic process ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / protein catabolic process at postsynapse / 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 / 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 / dorsal/ventral neural tube patterning / regulation of synaptic vesicle cycle / neural retina development / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / regulation of phosphorylation / metanephros development / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / glutamate receptor signaling pathway / locomotion / smooth endoplasmic reticulum calcium ion homeostasis / amyloid precursor protein metabolic process / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / aggresome / regulation of long-term synaptic potentiation / skeletal system morphogenesis / embryonic limb morphogenesis / cell fate specification / ciliary rootlet / myeloid cell homeostasis / regulation of postsynapse organization / azurophil granule membrane / regulation of neuron projection development / G protein-coupled dopamine receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / positive regulation of amyloid fibril formation / Golgi cisterna membrane / adult behavior / positive regulation of dendritic spine development / positive regulation of receptor recycling / mitochondrial transport / positive regulation of catalytic activity / blood vessel development / heart looping / protein glycosylation / cerebral cortex cell migration / amyloid precursor protein catabolic process / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / autophagosome assembly / endopeptidase activator activity / EPH-ephrin mediated repulsion of cells / smooth endoplasmic reticulum / neuron development / hematopoietic progenitor cell differentiation / somitogenesis / T cell proliferation / Nuclear signaling by ERBB4 / rough endoplasmic reticulum / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / NOTCH2 Activation and Transmission of Signal to the Nucleus / neuron projection maintenance / cellular response to calcium ion / positive regulation of glycolytic process / Degradation of the extracellular matrix / negative regulation of ubiquitin-dependent protein catabolic 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 / epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / PDZ domain binding / astrocyte activation / apoptotic signaling pathway / synapse organization / neuron migration Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / negative staining / Resolution: 5.4 Å | |||||||||
![]() | Lu PL / Bai XC / Ma D / Xie T / Yan CY / Sun LF / Yang GH / Zhao YY / Zhou R / Scheres SHW / Shi YG | |||||||||
![]() | ![]() Title: Three-dimensional structure of human γ-secretase. Authors: Peilong Lu / Xiao-Chen Bai / Dan Ma / Tian Xie / Chuangye Yan / Linfeng Sun / Guanghui Yang / Yanyu Zhao / Rui Zhou / Sjors H W Scheres / Yigong Shi / ![]() ![]() Abstract: The γ-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. ...The γ-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Aberrant cleavage of the amyloid precursor protein (APP) results in aggregation of amyloid-β, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human γ-secretase complex at 4.5 Å resolution, determined by cryo-electron-microscopy single-particle analysis. The γ-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) from nicastrin, which sits immediately above the hollow space formed by the TM horseshoe. Intriguingly, nicastrin ECD is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA. This structure serves as an important basis for understanding the functional mechanisms of the γ-secretase complex. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 9.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 9.9 KB 9.9 KB | Display Display | ![]() |
Images | ![]() | 155.3 KB | ||
Others | ![]() ![]() ![]() | 9.8 MB 8 MB 8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 265.7 KB | Display | ![]() |
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Full document | ![]() | 264.8 KB | Display | |
Data in XML | ![]() | 5.2 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 5a63M ![]() 2677C ![]() 4upc M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Reconstruction of human gamma-secretase. The particles were selected by two-steps of 3D classification. This map has good density for the transmembrane domain. All the 19 TM helices and some of the linkers are visible. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.76 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Supplemental map: emd 2678 additional 1.map
File | emd_2678_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Supplemental map: emd 2678 half map 1.map
File | emd_2678_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Supplemental map: emd 2678 half map 2.map
File | emd_2678_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : human gamma-secretase
Entire | Name: human gamma-secretase |
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Components |
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-Supramolecule #1000: human gamma-secretase
Supramolecule | Name: human gamma-secretase / type: sample / ID: 1000 / Oligomeric state: Homotetramer / Number unique components: 1 |
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Molecular weight | Experimental: 170 KDa / Theoretical: 170 KDa |
-Macromolecule #1: gamma-secretase
Macromolecule | Name: gamma-secretase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Oligomeric state: Homotetramer / Recombinant expression: Yes |
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Source (natural) | Organism: ![]() |
Molecular weight | Experimental: 170 KDa / Theoretical: 170 KDa |
Recombinant expression | Organism: ![]() |
-Experimental details
-Structure determination
Method | negative staining, cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 6 mg/mL |
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Buffer | pH: 7.4 Details: 25 mM HEPES, pH 7.4, 150 mM NaCl and amphipol A8-35 |
Staining | Type: NEGATIVE / Details: cryo-EM |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 90 K / Instrument: FEI VITROBOT MARK IV / Method: Blot for 4S before plunging |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Temperature | Min: 80 K / Max: 90 K / Average: 85 K |
Date | Feb 26, 2014 |
Image recording | Category: CCD / Film or detector model: GATAN K2 (4k x 4k) / Digitization - Sampling interval: 5 µm / Number real images: 1471 / Average electron dose: 38 e/Å2 / Details: 15 frames were recorded during the imaging. |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Calibrated magnification: 28409 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 4.4 µm / Nominal defocus min: 1.4 µm / Nominal magnification: 64000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
CTF correction | Details: Each particle |
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Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 5.4 Å / Resolution method: OTHER / Software - Name: CTFFIND3, RELION Details: Use a newly developed statistical movie processing approach to compensate for beam-induced movement. Number images used: 37310 |