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Open data
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Basic information
Entry | Database: PDB / ID: 8hgh | ||||||
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Title | Structure of 2:2 PAPP-A.STC2 complex | ||||||
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![]() | HYDROLASE / metal binding protein | ||||||
Function / homology | ![]() 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 / detection of maltose stimulus / maltose transport complex / response to dexamethasone ...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 / detection of maltose stimulus / maltose transport complex / response to dexamethasone / carbohydrate transport / decidualization / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / endoplasmic reticulum unfolded protein response / embryo implantation / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / 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 / outer membrane-bounded periplasmic space / response to oxidative stress / periplasmic space / cell surface receptor signaling pathway / endoplasmic reticulum lumen / negative regulation of gene expression / DNA damage response / heme binding / perinuclear region of cytoplasm / enzyme binding / Golgi apparatus / endoplasmic reticulum / protein homodimerization activity / proteolysis / extracellular space / zinc ion binding / extracellular region / membrane Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.16 Å | ||||||
![]() | Zhong, Q.H. / Chu, H.L. / Wang, G.P. / Zhang, C. / Wei, Y. / Qiao, J. / Hang, J. | ||||||
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![]() | ![]() Title: Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2. Authors: Qihang Zhong / Honglei Chu / Guopeng Wang / Cheng Zhang / Rong Li / Fusheng Guo / Xinlu Meng / Xiaoguang Lei / Youli Zhou / Ruobing Ren / Lin Tao / Ningning Li / Ning Gao / Yuan Wei / Jie Qiao / Jing Hang / ![]() Abstract: Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed ...Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 591.4 KB | Display | ![]() |
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PDB format | ![]() | 467.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 34739MC ![]() 7y5nC ![]() 7y5qC ![]() 8hggC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 216398.344 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() Strain: K-12 / Gene: malE, b4034, JW3994, PAPPA / Production host: ![]() #2: Protein | Mass: 33298.688 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() #3: Chemical | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Structure of 2:2 PAPP-A/STC2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1200 nm / Nominal defocus min: 700 nm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 59.8 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.19.1_4122: / Classification: refinement | ||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 4.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 253671 / Symmetry type: POINT | ||||||||||||||||||||||||||||
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