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- EMDB-33621: Structure of 1:1 PAPP-A.ProMBP complex(half map) -

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Basic information

Entry
Database: EMDB / ID: EMD-33621
TitleStructure of 1:1 PAPP-A.ProMBP complex(half map)
Map data
Sample
  • Complex: Structure of 1:1 PAPP-A/ProMBP complex(half map)
    • Protein or peptide: Bone marrow proteoglycan
    • Protein or peptide: Pappalysin-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ZINC ION
  • Ligand: CALCIUM IONCalcium
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
Eosinophil major basic protein / Eosinophil major basic protein, C-type lectin-like domain / 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 ...Eosinophil major basic protein / Eosinophil major basic protein, C-type lectin-like domain / 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 / C-type lectin, conserved site / C-type lectin domain signature. / 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 / Lectin C-type domain / C-type lectin domain profile. / C-type lectin-like / C-type lectin (CTL) or carbohydrate-recognition domain (CRD) / C-type lectin-like/link domain superfamily / C-type lectin fold / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Bone marrow proteoglycan / Pappalysin-1
Similarity search - Component
Biological speciesHomo sapiens (human) / human (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.45 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
DepositionJun 17, 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_33621.png

Downloads & links

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Map

FileDownload / File: emd_33621.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.052 Å
Density
Contour LevelBy AUTHOR: 0.0112
Minimum - Maximum-0.102409296 - 0.16948408
Average (Standard dev.)0.00026162318 (±0.0036992375)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 269.312 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33621_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_33621_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 1:1 PAPP-A/ProMBP complex(half map)

EntireName: Structure of 1:1 PAPP-A/ProMBP complex(half map)
Components
  • Complex: Structure of 1:1 PAPP-A/ProMBP complex(half map)
    • Protein or peptide: Bone marrow proteoglycan
    • Protein or peptide: Pappalysin-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ZINC ION
  • Ligand: CALCIUM IONCalcium

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Supramolecule #1: Structure of 1:1 PAPP-A/ProMBP complex(half map)

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

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Macromolecule #1: Bone marrow proteoglycan

MacromoleculeName: Bone marrow proteoglycan / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: human (human)
Molecular weightTheoretical: 25.236564 KDa
SequenceString: MKLPLLLALL FGAVSALHLR SETSTFETPL GAKTLPEDEE TPEQEMEETP CRELEEEEEW GSGSEDASKK DGAVESISVP DMVDKNLTC PEEEDTVKVV GIPGCQTCRY LLVRSLQTFS QAWFTCRRCY RGNLVSIHNF NINYRIQCSV SALNQGQVWI G GRITGSGR ...String:
MKLPLLLALL FGAVSALHLR SETSTFETPL GAKTLPEDEE TPEQEMEETP CRELEEEEEW GSGSEDASKK DGAVESISVP DMVDKNLTC PEEEDTVKVV GIPGCQTCRY LLVRSLQTFS QAWFTCRRCY RGNLVSIHNF NINYRIQCSV SALNQGQVWI G GRITGSGR CRRFQWVDGS RWNFAYWAAH QPWSRGGHCV ALCTRGGHWR RAHCLRRLPF ICSY

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Macromolecule #2: Pappalysin-1

MacromoleculeName: Pappalysin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: pappalysin-1
Source (natural)Organism: human (human)
Molecular weightTheoretical: 172.475484 KDa
SequenceString: REARGATEEP SPPSRALYFS GRGEQLRLRA DLELPRDAFT LQVWLRAEGG QRSPAVITGL YDKCSYISRD RGWVVGIHTI SDQDNKDPR YFFSLKTDRA RQVTTINAHR SYLPGQWVYL AATYDGQFMK LYVNGAQVAT SGEQVGGIFS PLTQKCKVLM L GGSALNHN ...String:
REARGATEEP SPPSRALYFS GRGEQLRLRA DLELPRDAFT LQVWLRAEGG QRSPAVITGL YDKCSYISRD RGWVVGIHTI SDQDNKDPR YFFSLKTDRA RQVTTINAHR SYLPGQWVYL AATYDGQFMK LYVNGAQVAT SGEQVGGIFS PLTQKCKVLM L GGSALNHN YRGYIEHFSL WKVARTQREI LSDMETHGAH TALPQLLLQE NWDNVKHAWS PMKDGSSPKV EFSNAHGFLL DT SLEPPLC GQTLCDNTEV IASYNQLSSF RQPKVVRYRV VNLYEDDHKN PTVTREQVDF QHHQLAEAFK QYNISWELDV LEV SNSSLR RRLILANCDI SKIGDENCDP ECNHTLTGHD GGDCRHLRHP AFVKKQHNGV CDMDCNYERF NFDGGECCDP EITN VTQTC FDPDSPHRAY LDVNELKNIL KLDGSTHLNI FFAKSSEEEL AGVATWPWDK EALMHLGGIV LNPSFYGMPG HTHTM IHEI GHSLGLYHVF RGISEIQSCS DPCMETEPSF ETGDLCNDTN PAPKHKSCGD PGPGNDTCGF HSFFNTPYNN FMSYAD DDC TDSFTPNQVA RMHCYLDLVY QGWQPSRKPA PVALAPQVLG HTTDSVTLEW FPPIDGHFFE RELGSACHLC LEGRILV QY ASNASSPMPC SPSGHWSPRE AEGHPDVEQP CKSSVRTWSP NSAVNPHTVP PACPEPQGCY LELEFLYPLV PESLTIWV T FVSTDWDSSG AVNDIKLLAV SGKNISLGPQ NVFCDVPLTI RLWDVGEEVY GIQIYTLDEH LEIDAAMLTS TADTPLCLQ CKPLKYKVVR DPPLQMDVAS ILHLNRKFVD MDLNLGSVYQ YWVITISGTE ESEPSPAVTY IHGSGYCGDG IIQKDQGEQC DDMNKINGD GCSLFCRQEV SFNCIDEPSR CYFHDGDGVC EEFEQKTSIK DCGVYTPQGF LDQWASNASV SHQDQQCPGW V IIGQPAAS QVCRTKVIDL SEGISQHAWY PCTISYPYSQ LAQTTFWLRA YFSQPMVAAA VIVHLVTDGT YYGDQKQETI SV QLLDTKD QSHDLGLHVL SCRNNPLIIP VVHDLSQPFY HSQAVRVSFS SPLVAISGVA LRSFDNFDPV TLSSCQRGET YSP AEQSCV HFACEKTDCP ELAVENASLN CSSSDRYHGA QCTVSCRTGY VLQIRRDDEL IKSQTGPSVT VTCTEGKWNK QVAC EPVDC SIPDHHQVYA ASFSCPEGTT FGSQCSFQCR HPAQLKGNNS LLTCMEDGLW SFPEALCELM CLAPPPVPNA DLQTA RCRE NKHKVGSFCK YKCKPGYHVP GSSRKSKKRA FKTQCTQDGS WQEGACVPVT CDPPPPKFHG LYQCTNGFQF NSECRI KCE DSDASQGLGS NVIHCRKDGT WNGSFHVCQE MQGQCSVPNE LNSNLKLQCP DGYAIGSECA TSCLDHNSES IILPMNV TV RDIPHWLNPT RVERVVCTAG LKWYPHPALI HCVKGCEPFM GDNYCDAINN RAFCNYDGGD CCTSTVKTKK VTPFPMSC D LQGDCACRDP QAQEHSRKDL RGYSHG

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 7 / Formula: CA
Molecular weightTheoretical: 40.078 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
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 60.1 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 3D classificationSoftware - Name: RELION (ver. 3.1.2)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.2)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.2) / Number images used: 142469
FSC plot (resolution estimation)

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