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Yorodumi- PDB-5a63: Cryo-EM structure of the human gamma-secretase complex at 3.4 ang... -
+Open data
-Basic information
Entry | Database: PDB / ID: 5a63 | ||||||||||||
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Title | Cryo-EM structure of the human gamma-secretase complex at 3.4 angstrom resolution. | ||||||||||||
Components |
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Keywords | HYDROLASE / CRYO-EM / HUMAN GAMMA-SECRETASE / MEMBRANE PROTEIN | ||||||||||||
Function / homology | Function and homology information positive regulation of L-glutamate import across plasma membrane / Cajal-Retzius cell differentiation / amyloid precursor protein biosynthetic process / positive regulation of coagulation / protein catabolic process at postsynapse / 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 L-glutamate import across plasma membrane / Cajal-Retzius cell differentiation / amyloid precursor protein biosynthetic process / positive regulation of coagulation / protein catabolic process at postsynapse / 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 / choline transport / Noncanonical activation of NOTCH3 / positive regulation of endopeptidase activity / Notch receptor processing / central nervous system myelination / sequestering of calcium ion / membrane protein intracellular domain proteolysis / synaptic vesicle targeting / negative regulation of axonogenesis / regulation of resting membrane potential / T cell activation involved in immune response / skin morphogenesis / NOTCH4 Activation and Transmission of Signal to the Nucleus / growth factor receptor binding / neural retina development / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / amyloid precursor protein metabolic process / regulation of phosphorylation / metanephros development / locomotion / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / glutamate receptor signaling pathway / nuclear outer membrane / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / regulation of canonical Wnt signaling pathway / regulation of long-term synaptic potentiation / aggresome / embryonic limb morphogenesis / skeletal system morphogenesis / positive regulation of amyloid fibril formation / cell fate specification / regulation of postsynapse organization / positive regulation of dendritic spine development / ciliary rootlet / myeloid cell homeostasis / azurophil granule membrane / dopamine receptor signaling pathway / adult behavior / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / positive regulation of receptor recycling / mitochondrial transport / positive regulation of catalytic activity / heart looping / regulation of neuron projection development / blood vessel development / neuron development / smooth endoplasmic reticulum / amyloid precursor protein catabolic process / cerebral cortex cell migration / protein glycosylation / amyloid-beta formation / negative regulation of apoptotic signaling pathway / autophagosome assembly / membrane protein ectodomain proteolysis / endopeptidase activator activity / EPH-ephrin mediated repulsion of cells / Nuclear signaling by ERBB4 / hematopoietic progenitor cell differentiation / somitogenesis / amyloid-beta metabolic process / T cell proliferation / rough endoplasmic reticulum / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / NOTCH2 Activation and Transmission of Signal to the Nucleus / negative regulation of ubiquitin-dependent protein catabolic process / cellular response to calcium ion / neuron projection maintenance / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / Degradation of the extracellular matrix / positive regulation of glycolytic process / post-embryonic development / dendritic shaft / thymus development / negative regulation of protein phosphorylation / epithelial cell proliferation / PDZ domain binding / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / apoptotic signaling pathway / synapse organization Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||
Authors | Bai, X. / Yan, C. / Yang, G. / Lu, P. / Ma, D. / Sun, L. / Zhou, R. / Scheres, S.H.W. / Shi, Y. | ||||||||||||
Citation | Journal: Nature / Year: 2015 Title: An atomic structure of human γ-secretase. Authors: Xiao-Chen Bai / Chuangye Yan / Guanghui Yang / Peilong Lu / Dan Ma / Linfeng Sun / Rui Zhou / Sjors H W Scheres / Yigong Shi / Abstract: Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1) ...Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function. | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 5a63.cif.gz | 263 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5a63.ent.gz | 211.6 KB | Display | PDB format |
PDBx/mmJSON format | 5a63.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/a6/5a63 ftp://data.pdbj.org/pub/pdb/validation_reports/a6/5a63 | HTTPS FTP |
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-Related structure data
Related structure data | 2677M 2678M 3061MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10194 (Title: An atomic structure of human gamma-secretase / Data size: 11.7 TB Data #1: Unaligned multi-frame micrographs of human gamma-secretase [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 78483.570 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) / References: UniProt: Q92542 |
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#2: Protein | Mass: 52713.535 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: PSEN1, AD3, PS1, PSNL1 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) References: UniProt: P49768, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases |
-Gamma-secretase subunit ... , 2 types, 2 molecules CD
#3: Protein | Mass: 29017.943 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: APH1A, PSF, CGI-78, UNQ579/PRO1141 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) / References: UniProt: Q96BI3 |
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#4: Protein | Mass: 12038.029 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: PSENEN, PEN2, MDS033 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) / References: UniProt: Q9NZ42 |
-Sugars , 3 types, 11 molecules
#5: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #6: 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 | Source method: isolated from a genetically manipulated source #7: Sugar | ChemComp-NAG / |
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-Non-polymers , 1 types, 2 molecules
#8: Chemical |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: HUMAN GAMMA-SECRETASEGamma secretase / Type: COMPLEX |
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Buffer solution | Name: 25 MM HEPES, PH 7.4, 150 MM NACL AND AMPHIPOL A8-35 / pH: 7.4 Details: 25 MM HEPES, PH 7.4, 150 MM NACL AND AMPHIPOL A8-35 |
Specimen | Conc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: HOLEY CARBON |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE Details: VITRIFICATION 1 -- CRYOGEN- ETHANE, HUMIDITY- 100, TEMPERATURE- 85, INSTRUMENT- FEI VITROBOT MARK IV, METHOD- BLOT FOR 4 SECONDS BEFORE PLUNGING, |
-Electron microscopy imaging
Experimental equipment | Model: Tecnai F30 / Image courtesy: FEI Company |
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Microscopy | Model: FEI TECNAI F30 / Date: Oct 2, 2014 |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 81000 X / Calibrated magnification: 35714 X / Nominal defocus max: 3200 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm |
Specimen holder | Temperature: 85 K |
Image recording | Electron dose: 38 e/Å2 / Film or detector model: GATAN K2 (4k x 4k) |
Radiation wavelength | Relative weight: 1 |
-Processing
EM software |
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CTF correction | Details: EACH PARTICLE | ||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||
3D reconstruction | Resolution: 3.4 Å / Num. of particles: 159549 Magnification calibration: CROSS- -CORRELATION DENSITIES WITHIN SPHERICAL SHELL Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3061. (DEPOSITION ID: 13527). Symmetry type: POINT | ||||||||||||
Refinement | Highest resolution: 3.4 Å | ||||||||||||
Refinement step | Cycle: LAST / Highest resolution: 3.4 Å
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