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- EMDB-34739: Structure of 2:2 PAPP-A.STC2 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-34739
TitleStructure of 2:2 PAPP-A.STC2 complex
Map data
Sample
  • Complex: Structure of 2:2 PAPP-A/STC2 complex
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1
    • Protein or peptide: Stanniocalcin-2
  • Ligand: ZINC ION
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 / protein metabolic process / negative regulation of multicellular organism growth / detection of maltose stimulus / maltose binding / maltose transport complex ...regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / response to vitamin D / protein metabolic process / negative regulation of multicellular organism growth / detection of maltose stimulus / maltose binding / maltose transport complex / maltose transport / response to dexamethasone / maltodextrin transmembrane transport / carbohydrate transmembrane transporter activity / decidualization / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / carbohydrate transport / 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 / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / 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 / LamG-like jellyroll fold domain / Peptidase M43, pregnancy-associated plasma-A / Pregnancy-associated plasma protein-A / Concanavalin A-like lectin/glucanases superfamily / Notch domain ...Stanniocalcin / Stanniocalcin family / Pappalysin-1/2 / Myxococcus cysteine-rich repeat / LamG-like jellyroll fold / LamG-like jellyroll fold domain / Peptidase M43, pregnancy-associated plasma-A / Pregnancy-associated plasma protein-A / 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 speciesHomo sapiens (human) / human (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.16 Å
AuthorsZhong QH / Chu HL / Wang GP / Zhang C / Wei Y / Qiao J / Hang J
Funding support China, 1 items
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, 2022-
Header (metadata) releaseJan 11, 2023-
Map releaseJan 11, 2023-
UpdateJan 11, 2023-
Current statusJan 11, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34739.png

Downloads & links

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Map

FileDownload / File: emd_34739.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.055 Å
Density
Contour LevelBy AUTHOR: 0.0217
Minimum - Maximum-0.03856665 - 0.08226164
Average (Standard dev.)0.000420611 (±0.0027724204)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 270.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34739_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34739_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of 2:2 PAPP-A/STC2 complex

EntireName: Structure of 2:2 PAPP-A/STC2 complex
Components
  • Complex: Structure of 2:2 PAPP-A/STC2 complex
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1
    • Protein or peptide: Stanniocalcin-2
  • Ligand: ZINC ION

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Supramolecule #1: Structure of 2:2 PAPP-A/STC2 complex

SupramoleculeName: Structure of 2:2 PAPP-A/STC2 complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: pappalysin-1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 216.398344 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AASHHHHHHH HHHSGKIEEG KLVIWINGDK GYNGLAEVGK KFEKDTGIKV TVEHPDKLEE KFPQVAATGD GPDIIFWAHD RFGGYAQSG LLAEITPDKA FQDKLYPFTW DAVRYNGKLI AYPIAVEALS LIYNKDLLPN PPKTWEEIPA LDKELKAKGK S ALMFNLQE ...String:
AASHHHHHHH HHHSGKIEEG KLVIWINGDK GYNGLAEVGK KFEKDTGIKV TVEHPDKLEE KFPQVAATGD GPDIIFWAHD RFGGYAQSG LLAEITPDKA FQDKLYPFTW DAVRYNGKLI AYPIAVEALS LIYNKDLLPN PPKTWEEIPA LDKELKAKGK S ALMFNLQE PYFTWPLIAA DGGYAFKYEN GKYDIKDVGV DNAGAKAGLT FLVDLIKNKH MNADTDYSIA EAAFNKGETA MT INGPWAW SNIDTSKVNY GVTVLPTFKG QPSKPFVGVL SAGINAASPN KELAKEFLEN YLLTDEGLEA VNKDKPLGAV ALK SYEEEL AKDPRIAATM ENAQKGEIMP NIPQMSAFWY AVRTAVINAA SGRQTVDEAL KDAQTDYDIP TTENLYFQGE FREA RGATE EPSPPSRALY FSGRGEQLRL RADLELPRDA FTLQVWLRAE GGQRSPAVIT GLYDKCSYIS RDRGWVVGIH TISDQ DNKD PRYFFSLKTD RARQVTTINA HRSYLPGQWV YLAATYDGQF MKLYVNGAQV ATSGEQVGGI FSPLTQKCKV LMLGGS ALN HNYRGYIEHF SLWKVARTQR EILSDMETHG AHTALPQLLL QENWDNVKHA WSPMKDGSSP KVEFSNAHGF LLDTSLE PP LCGQTLCDNT EVIASYNQLS SFRQPKVVRY RVVNLYEDDH KNPTVTREQV DFQHHQLAEA FKQYNISWEL DVLEVSNS S LRRRLILANC DISKIGDENC DPECNHTLTG HDGGDCRHLR HPAFVKKQHN GVCDMDCNYE RFNFDGGECC DPEITNVTQ TCFDPDSPHR AYLDVNELKN ILKLDGSTHL NIFFAKSSEE ELAGVATWPW DKEALMHLGG IVLNPSFYGM PGHTHTMIHE IGHSLGLYH VFRGISEIQS CSDPCMETEP SFETGDLCND TNPAPKHKSC GDPGPGNDTC GFHSFFNTPY NNFMSYADDD C TDSFTPNQ VARMHCYLDL VYQGWQPSRK PAPVALAPQV LGHTTDSVTL EWFPPIDGHF FERELGSACH LCLEGRILVQ YA SNASSPM PCSPSGHWSP REAEGHPDVE QPCKSSVRTW SPNSAVNPHT VPPACPEPQG CYLELEFLYP LVPESLTIWV TFV STDWDS SGAVNDIKLL AVSGKNISLG PQNVFCDVPL TIRLWDVGEE VYGIQIYTLD EHLEIDAAML TSTADTPLCL QCKP LKYKV VRDPPLQMDV ASILHLNRKF VDMDLNLGSV YQYWVITISG TEESEPSPAV TYIHGSGYCG DGIIQKDQGE QCDDM NKIN GDGCSLFCRQ EVSFNCIDEP SRCYFHDGDG VCEEFEQKTS IKDCGVYTPQ GFLDQWASNA SVSHQDQQCP GWVIIG QPA ASQVCRTKVI DLSEGISQHA WYPCTISYPY SQLAQTTFWL RAYFSQPMVA AAVIVHLVTD GTYYGDQKQE TISVQLL DT KDQSHDLGLH VLSCRNNPLI IPVVHDLSQP FYHSQAVRVS FSSPLVAISG VALRSFDNFD PVTLSSCQRG ETYSPAEQ S CVHFACEKTD CPELAVENAS LNCSSSDRYH GAQCTVSCRT GYVLQIRRDD ELIKSQTGPS VTVTCTEGKW NKQVACEPV DCSIPDHHQV YAASFSCPEG TTFGSQCSFQ CRHPAQLKGN NSLLTCMEDG LWSFPEALCE LMCLAPPPVP NADLQTARCR ENKHKVGSF CKYKCKPGYH VPGSSRKSKK RAFKTQCTQD GSWQEGACVP VTCDPPPPKF HGLYQCTNGF QFNSECRIKC E DSDASQGL GSNVIHCRKD GTWNGSFHVC QEMQGQCSVP NELNSNLKLQ CPDGYAIGSE CATSCLDHNS ESIILPMNVT VR DIPHWLN PTRVERVVCT AGLKWYPHPA LIHCVKGCEP FMGDNYCDAI NNRAFCNYDG GDCCTSTVKT KKVTPFPMSC DLQ GDCACR DPQAQEHSRK DLRGYSHG

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Macromolecule #2: Stanniocalcin-2

MacromoleculeName: Stanniocalcin-2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: human (human)
Molecular weightTheoretical: 33.298688 KDa
SequenceString: MCAERLGQFM TLALVLATFD PARGTDATNP PEGPQDRSSQ QKGRLSLQNT AEIQHCLVNA GDVGCGVFEC FENNSCEIRG LHGICMTFL HNAGKFDAQG KSFIKDALKC KAHALRHRFG CISRKCPAIR EMVSQLQREC YLKHDLCAAA QENTRVIVEM I HFKDLLLH ...String:
MCAERLGQFM TLALVLATFD PARGTDATNP PEGPQDRSSQ QKGRLSLQNT AEIQHCLVNA GDVGCGVFEC FENNSCEIRG LHGICMTFL HNAGKFDAQG KSFIKDALKC KAHALRHRFG CISRKCPAIR EMVSQLQREC YLKHDLCAAA QENTRVIVEM I HFKDLLLH EPYVDLVNLL LTCGEEVKEA ITHSVQVQCE QNWGSLCSIL SFCTSAIQKP PTAPPERQPQ VDRTKLSRAH HG EAGHHLP EPSSRETGRG AKGERGSKSH PNAHARGRVG GLGAQGPSGS SEWEDEQSEY SDIRR

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.7000000000000001 µm
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 59.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.2)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.2)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.16 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.2) / Number images used: 253671
FSC plot (resolution estimation)

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