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Yorodumi- EMDB-38059: Cryo-EM structure of human gamma-secretase in complex with Abeta49 -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-38059 | |||||||||
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Title | Cryo-EM structure of human gamma-secretase in complex with Abeta49 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex | |||||||||
Function / homology | Function and homology information Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / 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 / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / 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 / protein catabolic process at postsynapse / 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 / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / cerebral cortex cell migration / regulation of phosphorylation / metanephros development / regulation of epidermal growth factor-activated receptor activity / brain morphogenesis / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / endoplasmic reticulum calcium ion homeostasis / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / nuclear outer membrane / glutamate receptor signaling pathway / locomotion / axon midline choice point recognition / amyloid precursor protein metabolic process / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / aggresome / regulation of long-term synaptic potentiation / regulation of spontaneous synaptic transmission / mating behavior / embryonic limb morphogenesis / skeletal system morphogenesis / cell fate specification / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / myeloid cell homeostasis / regulation of postsynapse organization / Lysosome Vesicle Biogenesis / azurophil granule membrane / PTB domain binding / G protein-coupled dopamine receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi-associated vesicle / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / Golgi cisterna membrane / adult behavior / positive regulation of G2/M transition of mitotic cell cycle / mitochondrial transport / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / positive regulation of dendritic spine development / positive regulation of receptor recycling / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / blood vessel development / regulation of neuron projection development / heart looping / protein glycosylation / dendrite development / amyloid precursor protein catabolic process / presynaptic active zone / modulation of excitatory postsynaptic potential / regulation of peptidyl-tyrosine phosphorylation / amyloid-beta formation / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / regulation of presynapse assembly Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Guo X / Yan C / Lei J / Zhou R / Shi Y / Jia B / Jing D | |||||||||
Funding support | China, 1 items
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Citation | Journal: Science / Year: 2024 Title: Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Authors: Xuefei Guo / Haotian Li / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi / Abstract: Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step ...Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43. In all cases, the substrate displays the same structural features: a transmembrane α-helix, a three-residue linker, and a β-strand that forms a hybrid β-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate β-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new β-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_38059.map.gz | 117.9 MB | EMDB map data format | |
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Header (meta data) | emd-38059-v30.xml emd-38059.xml | 20.2 KB 20.2 KB | Display Display | EMDB header |
Images | emd_38059.png | 132.6 KB | ||
Filedesc metadata | emd-38059.cif.gz | 7 KB | ||
Others | emd_38059_half_map_1.map.gz emd_38059_half_map_2.map.gz | 115.7 MB 115.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-38059 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38059 | HTTPS FTP |
-Validation report
Summary document | emd_38059_validation.pdf.gz | 774.6 KB | Display | EMDB validaton report |
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Full document | emd_38059_full_validation.pdf.gz | 774.1 KB | Display | |
Data in XML | emd_38059_validation.xml.gz | 14 KB | Display | |
Data in CIF | emd_38059_validation.cif.gz | 16.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38059 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38059 | HTTPS FTP |
-Related structure data
Related structure data | 8x52MC 8x53C 8x54C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_38059.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.0979 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_38059_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_38059_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human gamma-secretase in complex with Abeta49
Entire | Name: Human gamma-secretase in complex with Abeta49 |
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Components |
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-Supramolecule #1: Human gamma-secretase in complex with Abeta49
Supramolecule | Name: Human gamma-secretase in complex with Abeta49 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Amyloid-beta precursor protein
Macromolecule | Name: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 13.800604 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MDAEFRHDSG YEVHHQKLVF FAEDVGSNCG AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYEN PTYKFFEQMQ NEQKLISEED LLEHHHHHHH H UniProtKB: Amyloid-beta precursor protein |
-Macromolecule #2: Nicastrin
Macromolecule | Name: Nicastrin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 78.473555 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 SCNPEIV 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 |
-Macromolecule #3: Presenilin-1
Macromolecule | Name: Presenilin-1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO EC number: Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 52.712551 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 RGVKLGLGNF IFYSVLVGKA SATA SGDWN TTIACFVAIL IGLCLTLLLL AIFKKALPAL PISITFGLVF YFATDYLVQP FMDQLAFHQF YI UniProtKB: Presenilin-1 |
-Macromolecule #4: Gamma-secretase subunit APH-1A
Macromolecule | Name: Gamma-secretase subunit APH-1A / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 29.017943 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #5: Gamma-secretase subunit PEN-2
Macromolecule | Name: Gamma-secretase subunit PEN-2 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 12.038029 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MNLERVSNEE KLNLCRKYYL GGFAFLPFLW LVNIFWFFRE AFLVPAYTEQ SQIKGYVWRS AVGFLFWVIV LTSWITIFQI YRPRWGALG DYLSFTIPLG TP UniProtKB: Gamma-secretase subunit PEN-2 |
-Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 6 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #9: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 9 / Number of copies: 2 / Formula: PC1 |
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Molecular weight | Theoretical: 790.145 Da |
Chemical component information | ChemComp-PC1: |
-Macromolecule #10: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 10 / Number of copies: 2 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Startup model | Type of model: EMDB MAP EMDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 463727 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |