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- EMDB-17112: Structure of apo form of human gamma-secretase PSEN1 APH-1B isofo... -

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Entry
Database: EMDB / ID: EMD-17112
TitleStructure of apo form of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc
Map dataLocal resolution filtered masked map after pixel size calibration
Sample
  • Complex: Gamma secretase
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-1 CTF12
    • Protein or peptide: Gamma-secretase subunit APH-1B
    • Protein or peptide: Gamma-secretase subunit PEN-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Keywordsintramembrane proteolysis / protease / di-aspartyl protease / Alzheimer's disease / complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


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 / 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 / transport vesicle / 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
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 / Gamma-secretase subunit APH-1B / Nicastrin / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsOdorcic I / Chavez Gutierrez L / Efremov RG
Funding support Belgium, 4 items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO)G0B2519N Belgium
Research Foundation - Flanders (FWO)G008023N Belgium
Research Foundation - Flanders (FWO)G0H5916N Belgium
Research Foundation - Flanders (FWO)G054617N Belgium
CitationJournal: 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
DepositionApr 12, 2023-
Header (metadata) releaseApr 24, 2024-
Map releaseApr 24, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17112.png

Downloads & links

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Map

FileDownload / File: emd_17112.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal resolution filtered masked map after pixel size calibration
Voxel sizeX=Y=Z: 0.776 Å
Density
Contour LevelBy AUTHOR: 0.014
Minimum - Maximum-0.1530859 - 0.22286402
Average (Standard dev.)0.000048213333 (±0.0040431553)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 248.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17112_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: Sharpened map after pixel size calibration

Fileemd_17112_additional_1.map
AnnotationSharpened map after pixel size calibration
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: Half-map (2)

Fileemd_17112_half_map_1.map
AnnotationHalf-map (2)
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AxesZYX

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Histogram

Histogram (log scale)

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Half map: Half-map (1)

Fileemd_17112_half_map_2.map
AnnotationHalf-map (1)
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AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Gamma secretase

EntireName: Gamma secretase
Components
  • Complex: Gamma secretase
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-1 CTF12
    • Protein or peptide: Gamma-secretase subunit APH-1B
    • Protein or peptide: Gamma-secretase subunit PEN-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Supramolecule #1: Gamma secretase

SupramoleculeName: Gamma secretase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 172 KDa

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Macromolecule #1: Nicastrin

MacromoleculeName: Nicastrin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 79.371586 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG ...String:
MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG NGLAYEDFSF PIFLLEDENE TKVIKQCYQD HNLSQNGSAP TFPLCAMQLF SHMHAVISTA TCMRRSSIQS TF SINPEIV CDPLSDYNVW SMLKPINTTG TLKPDDRVVV AATRLDSRSF FWNVAPGAES AVASFVTQLA AAEALQKAPD VTT LPRNVM FVFFQGETFD YIGSSRMVYD MEKGKFPVQL ENVDSFVELG QVALRTSLEL WMHTDPVSQK NESVRNQVED LLAT LEKSG AGVPAVILRR PNQSQPLPPS SLQRFLRARN ISGVVLADHS GAFHNKYYQS IYDTAENINV SYPEWLSPEE DLNFV TDTA KALADVATVL GRALYELAGG TNFSDTVQAD PQTVTRLLYG FLIKANNSWF QSILRQDLRS YLGDGPLQHY IAVSSP TNT TYVVQYALAN LTGTVVNLTR EQCQDPSKVP SENKDLYEYS WVQGPLHSNE TDRLPRCVRS TARLARALSP AFELSQW SS TEYSTWTESR WKDIRARIFL IASKELELIT LTVGFGILIF SLIVTYCINA KADVLFIAPR EPGAVSYGTL EVLFQ

UniProtKB: Nicastrin

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Macromolecule #2: Presenilin-1 CTF12

MacromoleculeName: Presenilin-1 CTF12 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.713535 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII ...String:
MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII SSLLLLFFFS FIYLGEVFKT YNVAVDYITV ALLIWNFGVV GMISIHWKGP LRLQQAYLIM ISALMALVFI KY LPEWTAW LILAVISVYD LVAVLCPKGP LRMLVETAQE RNETLFPALI YSSTMVWLVN MAEGDPEAQR RVSKNSKYNA EST ERESQD TVAENDDGGF SEEWEAQRDS HLGPHRSTPE SRAAVQELSS SILAGEDPEE RGVKLGLGDF IFYSVLVGKA SATA SGDWN TTIACFVAIL IGLCLTLLLL AIFKKALPAL PISITFGLVF YFATDYLVQP FMDQLAFHQF YI

UniProtKB: Presenilin-1

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

MacromoleculeName: Gamma-secretase subunit APH-1B / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.480844 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MTAAVFFGCA FIAFGPALAL YVFTIATEPL RIIFLIAGAF FWLVSLLISS LVWFMARVII DNKDGPTQKY LLIFGAFVSV YIQEMFRFA YYKLLKKASE GLKSINPGET APSMRLLAYV SGLGFGIMSG VFSFVNTLSD SLGPGTVGIH GDSPQFFLYS A FMTLVIIL ...String:
MTAAVFFGCA FIAFGPALAL YVFTIATEPL RIIFLIAGAF FWLVSLLISS LVWFMARVII DNKDGPTQKY LLIFGAFVSV YIQEMFRFA YYKLLKKASE GLKSINPGET APSMRLLAYV SGLGFGIMSG VFSFVNTLSD SLGPGTVGIH GDSPQFFLYS A FMTLVIIL LHVFWGIVFF DGCEKKKWGI LLIVLLTHLL VSAQTFISSY YGINLASAFI ILVLMGTWAF LAAGGSCRSL KL CLLCQDK NFLLYNQRSR

UniProtKB: Gamma-secretase subunit APH-1B

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Macromolecule #4: Gamma-secretase subunit PEN-2

MacromoleculeName: Gamma-secretase subunit PEN-2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.038029 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MNLERVSNEE KLNLCRKYYL GGFAFLPFLW LVNIFWFFRE AFLVPAYTEQ SQIKGYVWRS AVGFLFWVIV LTSWITIFQI YRPRWGALG DYLSFTIPLG TP

UniProtKB: Gamma-secretase subunit PEN-2

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 7 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #8: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 3 / Formula: PC1
Molecular weightTheoretical: 790.145 Da
Chemical component information

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.04 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O6S2PIPES
100.0 mMNaClsodium chloride
GridModel: Quantifoil R0.6/1 / Material: COPPER / Mesh: 300 / Support film - #0 - Film type ID: 1 / Support film - #0 - Material: CARBON / Support film - #0 - topology: HOLEY / Support film - #1 - Film type ID: 2 / Support film - #1 - Material: GRAPHENE OXIDE / Support film - #1 - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 92 % / Chamber temperature: 296 K / Instrument: GATAN CRYOPLUNGE 3

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Specialist opticsEnergy filter - Name: In-column Omega Filter / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 10733 / Average exposure time: 3.0 sec. / Average electron dose: 61.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 1.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.55 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 60000
Sample stageSpecimen holder model: JEOL CRYOSPECPORTER / Cooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 986830
Startup modelType of model: OTHER / Details: ab initio model
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 111197
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 2 / Avg.num./class: 200000 / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5fn5

source_name: PDB, initial_model_type: experimental model
chain_id: C, source_name: Modeller, initial_model_type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8oqy:
Structure of apo form of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc

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