+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15220 | |||||||||
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Title | Partial dimer complex of PAPP-A and its inhibitor STC2 | |||||||||
Map data | Primary, sharpened map of a partial dimer of PAPP-A in complex with a STC2 subunit | |||||||||
Sample |
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Function / homology | Function and homology information regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / protein metabolic process / response to vitamin D / negative regulation of multicellular organism growth / response to dexamethasone / decidualization / endoplasmic reticulum unfolded protein response ...regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / protein metabolic process / response to vitamin D / negative regulation of multicellular organism growth / response to dexamethasone / decidualization / endoplasmic reticulum unfolded protein response / embryo implantation / female pregnancy / Post-translational protein phosphorylation / protein catabolic process / hormone activity / metalloendopeptidase activity / response to peptide hormone / intracellular calcium ion homeostasis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / metallopeptidase activity / cellular response to hypoxia / response to oxidative stress / cell surface receptor signaling pathway / endoplasmic reticulum lumen / negative regulation of gene expression / heme binding / perinuclear region of cytoplasm / enzyme binding / Golgi apparatus / endoplasmic reticulum / protein homodimerization activity / proteolysis / extracellular space / zinc ion binding / extracellular region Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.06 Å | |||||||||
Authors | Kobbero SD / Gajhede M / Mirza OA / Boesen T / Oxvig C | |||||||||
Funding support | Denmark, 1 items
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Citation | Journal: Nat Commun / Year: 2022 Title: Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Authors: Sara Dam Kobberø / Michael Gajhede / Osman Asghar Mirza / Søren Kløverpris / Troels Rønn Kjær / Jakob Hauge Mikkelsen / Thomas Boesen / Claus Oxvig / Abstract: The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single- ...The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single-particle cryo-electron microscopy (cryo-EM), we here report the structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2 (STC2), neither of which have been reported before. The highest resolution (3.1 Å) was obtained for the STC2 subunit and the N-terminal approximately 1000 residues of the PAPP-A subunit. The 500 kDa 2:2 PAPP-A·STC2 complex is a flexible multidomain ensemble with numerous interdomain contacts. In particular, a specific disulfide bond between the subunits of STC2 and PAPP-A prevents dissociation, and interactions between STC2 and a module located in the very C-terminal end of the PAPP-A subunit prevent binding of its main substrate, IGFBP-4. While devoid of activity towards IGFBP-4, the active site cleft of the catalytic domain is accessible in the inhibited PAPP-A·STC2 complex, as shown by its ability to hydrolyze a synthetic peptide derived from IGFBP-4. Relevant to multiple human pathologies, this unusual mechanism of proteolytic inhibition may support the development of specific pharmaceutical agents, by which IGF signaling can be indirectly modulated. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_15220.map.gz | 38.3 MB | EMDB map data format | |
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Header (meta data) | emd-15220-v30.xml emd-15220.xml | 28.5 KB 28.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_15220_fsc.xml | 7.2 KB | Display | FSC data file |
Images | emd_15220.png | 51.1 KB | ||
Others | emd_15220_additional_1.map.gz emd_15220_half_map_1.map.gz emd_15220_half_map_2.map.gz | 20.2 MB 37.7 MB 37.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15220 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15220 | HTTPS FTP |
-Validation report
Summary document | emd_15220_validation.pdf.gz | 712.2 KB | Display | EMDB validaton report |
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Full document | emd_15220_full_validation.pdf.gz | 711.8 KB | Display | |
Data in XML | emd_15220_validation.xml.gz | 14.8 KB | Display | |
Data in CIF | emd_15220_validation.cif.gz | 18.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15220 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15220 | HTTPS FTP |
-Related structure data
Related structure data | 8a7dMC 8a7eC 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_15220.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Primary, sharpened map of a partial dimer of PAPP-A in complex with a STC2 subunit | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.014 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Raw map of a partial dimer of PAPP-A in complex with a STC2 subunit
File | emd_15220_additional_1.map | ||||||||||||
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Annotation | Raw map of a partial dimer of PAPP-A in complex with a STC2 subunit | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map A of a partial dimer of...
File | emd_15220_half_map_1.map | ||||||||||||
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Annotation | Half map A of a partial dimer of PAPP-A in complex with a STC2 subunit | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map B of a partial dimer of...
File | emd_15220_half_map_2.map | ||||||||||||
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Annotation | Half map B of a partial dimer of PAPP-A in complex with a STC2 subunit | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Partial PAPP-A dimer in complex with subunit of its endogenous in...
+Supramolecule #1: Partial PAPP-A dimer in complex with subunit of its endogenous in...
+Supramolecule #2: PAPP-A
+Supramolecule #3: Subunit of Stanniocalcin-2
+Supramolecule #4: N-terminal part of PAPP-A
+Supramolecule #5: C-terminal part of PAPP-A
+Macromolecule #1: Pappalysin-1
+Macromolecule #2: Stanniocalcin-2
+Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #4: ZINC ION
+Macromolecule #5: CALCIUM ION
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.6 mg/mL | ||||||||||||
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Buffer | pH: 7.4 Component:
Details: Hepes buffer, 20 mM Hepes pH 7.4 100 mM NaCl, 1 mM CaCl | ||||||||||||
Grid | Model: C-flat-2/2 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277.15 K / Instrument: LEICA EM GP / Details: 4 s. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | #0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #0 - Number grids imaged: 1 / #0 - Number real images: 32144 / #0 - Average exposure time: 0.91 sec. / #0 - Average electron dose: 59.0 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - Number grids imaged: 1 / #1 - Number real images: 10060 / #1 - Average exposure time: 0.8 sec. / #1 - Average electron dose: 58.0 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: 0.6 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Details | alphafold2 model PAPP-A AF-Q13219-F1 STC2 AF-O76061-F1 |
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Refinement | Space: REAL / Protocol: RIGID BODY FIT |
Output model | PDB-8a7d: |