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- EMDB-2477: Negative stain electron microscopy structure of native human Pres... -

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Basic information

Entry
Database: EMDB / ID: EMD-2477
TitleNegative stain electron microscopy structure of native human Presenilin 1 (PS1) complex
Map dataNative human PS1 complex
Sample
  • Sample: native human Presenilin 1 (PS1) complex
  • Protein or peptide: Presenilin-1
  • Protein or peptide: Nicastrin
  • Protein or peptide: Gamma-secretase subunit APH-1AGamma secretase
  • Protein or peptide: Gamma-secretase subunit PEN-2Gamma secretase
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
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 / 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 / negative staining / Resolution: 17.4 Å
AuthorsLi Y / Lu S / Tsai CJ / Bohm C / Qamar S / Dodd RB / Meadows W / Jeon A / McLeod A / Chen F ...Li Y / Lu S / Tsai CJ / Bohm C / Qamar S / Dodd RB / Meadows W / Jeon A / McLeod A / Chen F / Arimon M / Berezovska O / Hyman BT / Tomita T / Iwatsubod T / Johnsof CM / Farrer L / Schmitt-Ulms G / Fraser P / St George-Hyslop P
CitationJournal: Structure / Year: 2014
Title: Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.
Authors: Yi Li / Stephen Hsueh-Jeng Lu / Ching-Ju Tsai / Christopher Bohm / Seema Qamar / Roger B Dodd / William Meadows / Amy Jeon / Adam McLeod / Fusheng Chen / Muriel Arimon / Oksana Berezovska / ...Authors: Yi Li / Stephen Hsueh-Jeng Lu / Ching-Ju Tsai / Christopher Bohm / Seema Qamar / Roger B Dodd / William Meadows / Amy Jeon / Adam McLeod / Fusheng Chen / Muriel Arimon / Oksana Berezovska / Bradley T Hyman / Taisuke Tomita / Takeshi Iwatsubo / Christopher M Johnson / Lindsay A Farrer / Gerold Schmitt-Ulms / Paul E Fraser / Peter H St George-Hyslop /
Abstract: Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been ...Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the "lateral gate" through which substrates access to the catalytic site.
History
DepositionSep 23, 2013-
Header (metadata) releaseNov 13, 2013-
Map releaseNov 20, 2013-
UpdateFeb 17, 2016-
Current statusFeb 17, 2016Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0165
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0165
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_2477.map.gz / Format: CCP4 / Size: 7.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNative human PS1 complex
Voxel sizeX=Y=Z: 2.04 Å
Density
Contour LevelBy AUTHOR: 0.0165 / Movie #1: 0.0165
Minimum - Maximum-0.02686341 - 0.04827741
Average (Standard dev.)-0.00017679 (±0.00506091)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 261.12 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.042.042.04
M x/y/z128128128
origin x/y/z0.0000.0000.000
length x/y/z261.120261.120261.120
α/β/γ90.00090.00090.000
start NX/NY/NZ00-40
NX/NY/NZ555581
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS128128128
D min/max/mean-0.0270.048-0.000

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Supplemental data

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Sample components

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Entire : native human Presenilin 1 (PS1) complex

EntireName: native human Presenilin 1 (PS1) complex
Components
  • Sample: native human Presenilin 1 (PS1) complex
  • Protein or peptide: Presenilin-1
  • Protein or peptide: Nicastrin
  • Protein or peptide: Gamma-secretase subunit APH-1AGamma secretase
  • Protein or peptide: Gamma-secretase subunit PEN-2Gamma secretase

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Supramolecule #1000: native human Presenilin 1 (PS1) complex

SupramoleculeName: native human Presenilin 1 (PS1) complex / type: sample / ID: 1000 / Details: The sample was monodisperse / Oligomeric state: 1:1:1:1 / Number unique components: 4
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Presenilin-1

MacromoleculeName: Presenilin-1 / type: protein_or_peptide / ID: 1 / Name.synonym: Protein S182
Details: N-terminus as tagged with TAP tag composed of Protein G and Streptavidin binding peptide tags separated by tobacco etch virus protease cleavage site
Number of copies: 1 / Recombinant expression: Yes
Source (natural)Organism: Homo sapiens (human) / synonym: human
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293
SequenceUniProtKB: Presenilin-1

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Macromolecule #2: Nicastrin

MacromoleculeName: Nicastrin / type: protein_or_peptide / ID: 2 / Name.synonym: KIAA0253 / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK293
SequenceUniProtKB: Nicastrin

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Macromolecule #3: Gamma-secretase subunit APH-1A

MacromoleculeName: Gamma-secretase subunit APH-1A / type: protein_or_peptide / ID: 3 / Name.synonym: Aph-1alpha / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK293
SequenceUniProtKB: Gamma-secretase subunit APH-1A

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Macromolecule #4: Gamma-secretase subunit PEN-2

MacromoleculeName: Gamma-secretase subunit PEN-2 / type: protein_or_peptide / ID: 4 / Name.synonym: Presenilin enhancer protein 2 / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK293
SequenceUniProtKB: Gamma-secretase subunit PEN-2

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.02 mg/mL
BufferpH: 7.4
Details: 50 mM Tris-HCl, 150 mM NaCl, 2 mM EDTA, 5 mM MgCl2, 5 mM CaCl2
StainingType: NEGATIVE
Details: Grids with adsorbed protein floated on 1% w/v uranyl acetate for 2-10 seconds
GridDetails: Carbon-coated 400-mesh copper grids were glow discharged in air at 600-700 V for 30-60 seconds on an Edward S150B sputter coater.
VitrificationCryogen name: NONE / Instrument: OTHER

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Electron microscopy

MicroscopeFEI TECNAI 12
Electron beamAcceleration voltage: 120 kV / Electron source: TUNGSTEN HAIRPIN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2 mm / Nominal defocus max: 1.0 µm
Sample stageSpecimen holder model: OTHER
DateNov 19, 2009
Image recordingCategory: CCD / Film or detector model: TVIPS TEMCAM-F224 (2k x 2k) / Number real images: 300

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 17.4 Å / Resolution method: OTHER / Software - Name: EMAN2, RELION / Number images used: 11234
DetailsThe particles were selected using EMAN2

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