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- EMDB-2677: Three-dimensional structure of human gamma-secretase at 4.5 angst... -

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Entry
Database: EMDB / ID: EMD-2677
TitleThree-dimensional structure of human gamma-secretase at 4.5 angstrom resolution
Map dataReconstruction of human gamma-secretase. The particles were selected by one-step of 3D classification. This map has good density for Nicastrin extracellular domain, but slightly worse density for transmembrane domain.
Sample
  • Sample: human gamma-secretase
  • Protein or peptide: human gamma-secretase
Keywordshuman gamma-secretase / cryo EM
Function / homology
Function and homology information


positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / Notch receptor processing / skin morphogenesis / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus ...positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / Notch receptor processing / skin morphogenesis / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus / ciliary rootlet / neural retina development / Regulated proteolysis of p75NTR / mitochondria-associated endoplasmic reticulum membrane contact site / aggresome / amyloid precursor protein metabolic process / endoplasmic reticulum calcium ion homeostasis / regulation of synaptic vesicle cycle / regulation of postsynapse organization / astrocyte activation involved in immune response / regulation of neuron projection development / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / regulation of canonical Wnt signaling pathway / Golgi cisterna membrane / growth factor receptor binding / azurophil granule membrane / positive regulation of amyloid fibril formation / positive regulation of dendritic spine development / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / smooth endoplasmic reticulum / positive regulation of receptor recycling / nuclear outer membrane / EPH-ephrin mediated repulsion of cells / cerebellum development / Notch signaling pathway / negative regulation of ubiquitin-dependent protein catabolic process / Nuclear signaling by ERBB4 / endopeptidase activator activity / calcium ion homeostasis / Degradation of the extracellular matrix / rough endoplasmic reticulum / neuron projection maintenance / astrocyte activation / positive regulation of glycolytic process / NOTCH2 Activation and Transmission of Signal to the Nucleus / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / protein processing / PDZ domain binding / neuromuscular junction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cell-cell adhesion / memory / synapse organization / sarcolemma / beta-catenin binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / cellular response to amyloid-beta / calcium channel activity / kinetochore / positive regulation of tumor necrosis factor production / melanosome / regulation of gene expression / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / synaptic vesicle / nuclear membrane / ATPase binding / growth cone / presynaptic membrane / early endosome membrane / endopeptidase activity / cell cortex / aspartic-type endopeptidase activity / molecular adaptor activity / early endosome / learning or memory / protein-macromolecule adaptor activity / postsynapse / endosome membrane / neuron projection / mitochondrial inner membrane / intracellular signal transduction / cadherin binding / membrane raft / Amyloid fiber formation / negative regulation of gene expression / Golgi membrane / lysosomal membrane / focal adhesion / apoptotic process / neuronal cell body / centrosome / positive regulation of gene expression / negative regulation of apoptotic process / Neutrophil degranulation
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
Presenilin-1 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / negative staining / Resolution: 4.5 Å
AuthorsLu PL / Bai XC / Ma D / Xie T / Yan CY / Sun LF / Yang GH / Zhao YY / Zhou R / Scheres SHW / Shi YG
CitationJournal: Nature / Year: 2014
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
DepositionJun 14, 2014-
Header (metadata) releaseJun 25, 2014-
Map releaseJul 9, 2014-
UpdateAug 19, 2015-
Current statusAug 19, 2015Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.12
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.12
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5a63
  • Surface level: 0.12
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

EMD-2677.png

Downloads & links

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Map

FileDownload / File: emd_2677.map.gz / Format: CCP4 / Size: 10.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationReconstruction of human gamma-secretase. The particles were selected by one-step of 3D classification. This map has good density for Nicastrin extracellular domain, but slightly worse density for transmembrane domain.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.76 Å/pix.
x 140 pix.
= 246.4 Å		1.76 Å/pix.
x 140 pix.
= 246.4 Å		1.76 Å/pix.
x 140 pix.
= 246.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.76 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12 / Movie #1: 0.12
Minimum - Maximum-0.24971597 - 0.41268069
Average (Standard dev.)0.00005459 (±0.02389037)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions140140140
Spacing140140140
CellA=B=C: 246.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.761.761.76
M x/y/z140140140
origin x/y/z0.0000.0000.000
length x/y/z246.400246.400246.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS140140140
D min/max/mean-0.2500.4130.000

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Supplemental data

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Supplemental map: emd 2677 additional 1.map

Fileemd_2677_additional_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Supplemental map: emd 2677 half map 1.map

Fileemd_2677_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Supplemental map: emd 2677 half map 2.map

Fileemd_2677_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human gamma-secretase

EntireName: human gamma-secretase
Components
  • Sample: human gamma-secretase
  • Protein or peptide: human gamma-secretase

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Supramolecule #1000: human gamma-secretase

SupramoleculeName: human gamma-secretase / type: sample / ID: 1000 / Oligomeric state: tetramer / Number unique components: 1
Molecular weightExperimental: 170 KDa / Theoretical: 170 KDa

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Macromolecule #1: human gamma-secretase

MacromoleculeName: human gamma-secretase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Oligomeric state: tetramer / Recombinant expression: Yes
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK 293F
Molecular weightExperimental: 170 KDa / Theoretical: 170 KDa
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK 293F / Recombinant plasmid: pMLink

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Experimental details

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Structure determination

Methodnegative staining, cryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration6 mg/mL
BufferpH: 7.4
Details: 25 mM HEPES, pH 7.4, 150 mM NaCl and amphipol A8-35
StainingType: NEGATIVE / Details: cryo-EM
VitrificationCryogen 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

MicroscopeFEI TITAN KRIOS
TemperatureMin: 80 K / Max: 90 K / Average: 85 K
DateFeb 26, 2014
Image recordingCategory: 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 beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated 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 stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionDetails: Each particle
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.5 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: 144545

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