+Open data
-Basic information
Entry | Database: PDB / ID: 8hgg | ||||||
---|---|---|---|---|---|---|---|
Title | Structure of 2:2 PAPP-A.ProMBP complex | ||||||
Components |
| ||||||
Keywords | HYDROLASE / METAL BINDING PROTEIN / Complex | ||||||
Function / homology | Function and homology information extracellular matrix structural constituent conferring compression resistance / defense response to nematode / pappalysin-1 / response to follicle-stimulating hormone / negative regulation of macrophage cytokine production / protein metabolic process / negative regulation of interleukin-10 production / response to dexamethasone / positive regulation of interleukin-4 production / transport vesicle ...extracellular matrix structural constituent conferring compression resistance / defense response to nematode / pappalysin-1 / response to follicle-stimulating hormone / negative regulation of macrophage cytokine production / protein metabolic process / negative regulation of interleukin-10 production / response to dexamethasone / positive regulation of interleukin-4 production / transport vesicle / female pregnancy / protein catabolic process / metalloendopeptidase activity / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / heparin binding / carbohydrate binding / collagen-containing extracellular matrix / ficolin-1-rich granule lumen / cell surface receptor signaling pathway / defense response to bacterium / immune response / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å | ||||||
Authors | Zhong, Q.H. / Chu, H.L. / Wang, G.P. / Zhang, C. / Wei, Y. / Qiao, J. / Hang, J. | ||||||
Funding support | China, 1items
| ||||||
Citation | Journal: Cell Discov / Year: 2022 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 |
|
-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
---|
-Downloads & links
-Download
PDBx/mmCIF format | 8hgg.cif.gz | 563.6 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb8hgg.ent.gz | 454 KB | Display | PDB format |
PDBx/mmJSON format | 8hgg.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/hg/8hgg ftp://data.pdbj.org/pub/pdb/validation_reports/hg/8hgg | HTTPS FTP |
---|
-Related structure data
Related structure data | 34738MC 7y5nC 7y5qC 8hghC M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
#1: Protein | Mass: 25236.564 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P13727 #2: Protein | Mass: 181175.609 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q13219 #3: Chemical | Has ligand of interest | Y | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Structure of 2:2 PAPP-A/ProMBP complex / Type: COMPLEX / Entity ID: #1-#2 / Source: NATURAL |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
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 |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1200 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 60.1 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.1_4122: / Classification: refinement | ||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EM software |
| ||||||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 261371 / Symmetry type: POINT | ||||||||||||||||||||||||||||
Refine LS restraints |
|