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- EMDB-36948: Human gamma-secretase in complex with a substrate mimetic -

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Entry
Database: EMDB / ID: EMD-36948
TitleHuman gamma-secretase in complex with a substrate mimetic
Map data
Sample
  • Complex: Human gamma-secretase
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-1
    • Protein or peptide: Gamma-secretase subunit APH-1A
    • Protein or peptide: Gamma-secretase subunit PEN-2
  • Protein or peptide: ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
KeywordsComplex / protease / substrate mimetic / MEMBRANE PROTEIN
Function / homology
Function and homology information


Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of endopeptidase activity / gamma-secretase complex / short-term synaptic potentiation / aspartic endopeptidase activity, intramembrane cleaving / positive regulation of amyloid precursor protein biosynthetic process / smooth endoplasmic reticulum calcium ion homeostasis ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of endopeptidase activity / gamma-secretase complex / short-term synaptic potentiation / aspartic endopeptidase activity, intramembrane cleaving / positive regulation of amyloid precursor protein biosynthetic process / smooth endoplasmic reticulum calcium ion homeostasis / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / synaptic vesicle targeting / positive regulation of coagulation / central nervous system myelination / negative regulation of axonogenesis / membrane protein intracellular domain proteolysis / skin morphogenesis / choline transport / T cell activation involved in immune response / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / ciliary rootlet / neural retina development / regulation of resting membrane potential / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / myeloid dendritic cell differentiation / regulation of phosphorylation / metanephros development / endoplasmic reticulum calcium ion homeostasis / brain morphogenesis / locomotion / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / regulation of postsynapse organization / astrocyte activation involved in immune response / embryonic limb morphogenesis / cell fate specification / regulation of canonical Wnt signaling pathway / aggresome / myeloid cell homeostasis / growth factor receptor binding / skeletal system morphogenesis / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / azurophil granule membrane / Golgi cisterna membrane / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / positive regulation of amyloid fibril formation / : / blood vessel development / amyloid-beta formation / mitochondrial transport / amyloid precursor protein catabolic process / heart looping / regulation of neuron projection development / positive regulation of dendritic spine development / adult behavior / cerebral cortex cell migration / smooth endoplasmic reticulum / positive regulation of receptor recycling / nuclear outer membrane / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / negative regulation of ubiquitin-dependent protein catabolic process / EPH-ephrin mediated repulsion of cells / autophagosome assembly / endopeptidase activator activity / neuron development / somitogenesis / hematopoietic progenitor cell differentiation / T cell proliferation / regulation of synaptic transmission, glutamatergic / Nuclear signaling by ERBB4 / calcium ion homeostasis / rough endoplasmic reticulum / Degradation of the extracellular matrix / Notch signaling pathway / neuron projection maintenance / astrocyte activation / NOTCH2 Activation and Transmission of Signal to the Nucleus / NRIF signals cell death from the nucleus / cellular response to calcium ion / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / thymus development / positive regulation of glycolytic process / dendritic shaft / epithelial cell proliferation / post-embryonic development / PDZ domain binding / NOTCH3 Activation and Transmission of Signal to the Nucleus / neuromuscular junction / apoptotic signaling pathway / cell-cell adhesion
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) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsShi YG / Zhou R / Wolfe MS
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81920108015 China
CitationJournal: Cell Rep / Year: 2024
Title: Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.
Authors: Sujan Devkota / Rui Zhou / Vaishnavi Nagarajan / Masato Maesako / Hung Do / Arshad Noorani / Caitlin Overmeyer / Sanjay Bhattarai / Justin T Douglas / Anita Saraf / Yinglong Miao / Brian D ...Authors: Sujan Devkota / Rui Zhou / Vaishnavi Nagarajan / Masato Maesako / Hung Do / Arshad Noorani / Caitlin Overmeyer / Sanjay Bhattarai / Justin T Douglas / Anita Saraf / Yinglong Miao / Brian D Ackley / Yigong Shi / Michael S Wolfe /
Abstract: Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide ...Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis.
History
DepositionJul 29, 2023-
Header (metadata) releaseJan 31, 2024-
Map releaseJan 31, 2024-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36948.png

Downloads & links

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Map

FileDownload / File: emd_36948.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 320 pix.
= 346.4 Å		1.08 Å/pix.
x 320 pix.
= 346.4 Å		1.08 Å/pix.
x 320 pix.
= 346.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0128
Minimum - Maximum-0.019394487 - 0.065142624
Average (Standard dev.)0.00016921095 (±0.0016169433)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 346.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_36948_msk_1.map
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Half map: #2

Fileemd_36948_half_map_1.map
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Half map: #1

Fileemd_36948_half_map_2.map
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Sample components

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Entire : Human gamma-secretase

EntireName: Human gamma-secretase
Components
  • Complex: Human gamma-secretase
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-1
    • Protein or peptide: Gamma-secretase subunit APH-1A
    • Protein or peptide: Gamma-secretase subunit PEN-2
  • Protein or peptide: ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL

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Supramolecule #1: Human gamma-secretase

SupramoleculeName: Human gamma-secretase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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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: 78.48357 KDa
Recombinant expressionOrganism: Homo sapiens (human)
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 EPGAVSY

UniProtKB: Nicastrin

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Macromolecule #2: Presenilin-1

MacromoleculeName: Presenilin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.713535 KDa
Recombinant expressionOrganism: Homo sapiens (human)
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-1A

MacromoleculeName: Gamma-secretase subunit APH-1A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.017943 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII ...String:
MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII LLHTFWGVVF FDACERRRYW ALGLVVGSHL LTSGLTFLNP WYEASLLPIY AVTVSMGLWA FITAGGSLRS IQ RSLLCRR QEDSRVMVYS ALRIPPED

UniProtKB: 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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.038029 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MNLERVSNEE KLNLCRKYYL GGFAFLPFLW LVNIFWFFRE AFLVPAYTEQ SQIKGYVWRS AVGFLFWVIV LTSWITIFQI YRPRWGALG DYLSFTIPLG TP

UniProtKB: Gamma-secretase subunit PEN-2

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Macromolecule #5: ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-V...

MacromoleculeName: ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.864298 KDa
SequenceString:
(ZQN)G(AIB)VVI(AIB)FV(AIB) GGGV(JUU)LV(NH2)

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #9: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 9 / Number of copies: 1 / 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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Macromolecule #10: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 10 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6iyc

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 349532
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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