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- PDB-8hgh: Structure of 2:2 PAPP-A.STC2 complex -

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Basic information

Entry
Database: PDB / ID: 8hgh
TitleStructure of 2:2 PAPP-A.STC2 complex
Components
  • Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1
  • Stanniocalcin-2
KeywordsHYDROLASE / metal binding protein
Function / homology
Function and homology information


regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / response to vitamin D / negative regulation of multicellular organism growth / detection of maltose stimulus / response to dexamethasone / maltose transport complex / maltose binding ...regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / response to vitamin D / negative regulation of multicellular organism growth / detection of maltose stimulus / response to dexamethasone / maltose transport complex / maltose binding / carbohydrate transport / maltose transport / maltodextrin transmembrane transport / decidualization / carbohydrate transmembrane transporter activity / 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 / outer membrane-bounded periplasmic space / cellular response to hypoxia / 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 / Golgi apparatus / enzyme binding / endoplasmic reticulum / protein homodimerization activity / proteolysis / extracellular space / zinc ion binding / extracellular region / membrane
Similarity search - Function
Stanniocalcin / Stanniocalcin family / Pappalysin-1/2 / Myxococcus cysteine-rich repeat / LamG-like jellyroll fold / Peptidase M43, pregnancy-associated plasma-A / Pregnancy-associated plasma protein-A / LamG-like jellyroll fold domain / Concanavalin A-like lectin/glucanases superfamily / Notch domain ...Stanniocalcin / Stanniocalcin family / Pappalysin-1/2 / Myxococcus cysteine-rich repeat / LamG-like jellyroll fold / Peptidase M43, pregnancy-associated plasma-A / Pregnancy-associated plasma protein-A / LamG-like jellyroll fold domain / Concanavalin A-like lectin/glucanases superfamily / Notch domain / Domain found in Notch and Lin-12 / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Metallopeptidase, catalytic domain superfamily / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Neutral zinc metallopeptidases, zinc-binding region signature. / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Stanniocalcin-2 / Maltose/maltodextrin-binding periplasmic protein / Pappalysin-1
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.16 Å
AuthorsZhong, Q.H. / Chu, H.L. / Wang, G.P. / Zhang, C. / Wei, Y. / Qiao, J. / Hang, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82071658 China
CitationJournal: 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
DepositionNov 14, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1
B: Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1
C: Stanniocalcin-2
G: Stanniocalcin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)499,5256
Polymers499,3944
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Insulin-like growth factor- ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Insulin-like growth factor-dependent IGF-binding protein 4 protease / IGF-dependent IGFBP-4 protease / IGFBP-4ase / Pregnancy-associated plasma protein A / PAPP-A


Mass: 216398.344 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Homo sapiens (human)
Strain: K-12 / Gene: malE, b4034, JW3994, PAPPA / Production host: Homo sapiens (human) / References: UniProt: P0AEX9, UniProt: Q13219, pappalysin-1
#2: Protein Stanniocalcin-2 / STC-2 / Stanniocalcin-related protein / STC-related protein / STCRP


Mass: 33298.688 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: O76061
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of 2:2 PAPP-A/STC2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1200 nm / Nominal defocus min: 700 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 59.8 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM software
IDNameVersionCategory
1RELION3.1.2particle selection
2SerialEMimage acquisition
10RELION3.1.2initial Euler assignment
11RELION3.1.2final Euler assignment
12RELION3.1.2classification
13RELION3.1.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 253671 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00326148
ELECTRON MICROSCOPYf_angle_d0.56635556
ELECTRON MICROSCOPYf_dihedral_angle_d12.0319502
ELECTRON MICROSCOPYf_chiral_restr0.0453848
ELECTRON MICROSCOPYf_plane_restr0.0054688

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