+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-34738 | |||||||||
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Title | Structure of 2:2 PAPP-A.ProMBP complex | |||||||||
Map data | ||||||||||
Sample |
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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 / positive regulation of interleukin-4 production / response to dexamethasone / 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 / positive regulation of interleukin-4 production / response to dexamethasone / transport vesicle / female pregnancy / protein catabolic process / metalloendopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / metallopeptidase activity / 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 / zinc ion binding / extracellular exosome / extracellular region Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / human (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.64 Å | |||||||||
Authors | Zhong QH / Chu HL / Wang GP / Zhang C / Wei Y / Qiao J / Hang J | |||||||||
Funding support | China, 1 items
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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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_34738.map.gz | 8.3 MB | EMDB map data format | |
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Header (meta data) | emd-34738-v30.xml emd-34738.xml | 18 KB 18 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_34738_fsc.xml | 9.1 KB | Display | FSC data file |
Images | emd_34738.png | 65 KB | ||
Others | emd_34738_half_map_1.map.gz emd_34738_half_map_2.map.gz | 48.3 MB 48.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-34738 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34738 | HTTPS FTP |
-Validation report
Summary document | emd_34738_validation.pdf.gz | 591.5 KB | Display | EMDB validaton report |
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Full document | emd_34738_full_validation.pdf.gz | 591 KB | Display | |
Data in XML | emd_34738_validation.xml.gz | 16.1 KB | Display | |
Data in CIF | emd_34738_validation.cif.gz | 21.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34738 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34738 | HTTPS FTP |
-Related structure data
Related structure data | 8hggMC 7y5nC 7y5qC 8hghC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_34738.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.052 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_34738_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34738_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Structure of 2:2 PAPP-A/ProMBP complex
Entire | Name: Structure of 2:2 PAPP-A/ProMBP complex |
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Components |
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-Supramolecule #1: Structure of 2:2 PAPP-A/ProMBP complex
Supramolecule | Name: Structure of 2:2 PAPP-A/ProMBP complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Bone marrow proteoglycan
Macromolecule | Name: Bone marrow proteoglycan / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: human (human) |
Molecular weight | Theoretical: 25.236564 KDa |
Sequence | String: 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 |
-Macromolecule #2: Pappalysin-1
Macromolecule | Name: Pappalysin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: human (human) |
Molecular weight | Theoretical: 181.175609 KDa |
Sequence | String: MRLWSWVLHL GLLSAALGCG LAERPRRARR DPRAGRPPRP AAGPATCATR AARGRRASPP PPPPPGGAWE AVRVPRRRQQ REARGATEE PSPPSRALYF SGRGEQLRLR ADLELPRDAF TLQVWLRAEG GQRSPAVITG LYDKCSYISR DRGWVVGIHT I SDQDNKDP ...String: MRLWSWVLHL GLLSAALGCG LAERPRRARR DPRAGRPPRP AAGPATCATR AARGRRASPP PPPPPGGAWE AVRVPRRRQQ REARGATEE PSPPSRALYF SGRGEQLRLR ADLELPRDAF TLQVWLRAEG GQRSPAVITG LYDKCSYISR DRGWVVGIHT I SDQDNKDP RYFFSLKTDR ARQVTTINAH RSYLPGQWVY LAATYDGQFM KLYVNGAQVA TSGEQVGGIF SPLTQKCKVL ML GGSALNH NYRGYIEHFS LWKVARTQRE ILSDMETHGA HTALPQLLLQ ENWDNVKHAW SPMKDGSSPK VEFSNAHGFL LDT SLEPPL CGQTLCDNTE VIASYNQLSS FRQPKVVRYR VVNLYEDDHK NPTVTREQVD FQHHQLAEAF KQYNISWELD VLEV SNSSL RRRLILANCD ISKIGDENCD PECNHTLTGH DGGDCRHLRH PAFVKKQHNG VCDMDCNYER FNFDGGECCD PEITN VTQT CFDPDSPHRA YLDVNELKNI LKLDGSTHLN IFFAKSSEEE LAGVATWPWD KEALMHLGGI VLNPSFYGMP GHTHTM IHE IGHSLGLYHV FRGISEIQSC SDPCMETEPS FETGDLCNDT NPAPKHKSCG DPGPGNDTCG FHSFFNTPYN NFMSYAD DD CTDSFTPNQV ARMHCYLDLV YQGWQPSRKP APVALAPQVL GHTTDSVTLE WFPPIDGHFF ERELGSACHL CLEGRILV Q YASNASSPMP CSPSGHWSPR EAEGHPDVEQ PCKSSVRTWS PNSAVNPHTV PPACPEPQGC YLELEFLYPL VPESLTIWV TFVSTDWDSS GAVNDIKLLA VSGKNISLGP QNVFCDVPLT IRLWDVGEEV YGIQIYTLDE HLEIDAAMLT STADTPLCLQ CKPLKYKVV RDPPLQMDVA SILHLNRKFV DMDLNLGSVY QYWVITISGT EESEPSPAVT YIHGSGYCGD GIIQKDQGEQ C DDMNKING DGCSLFCRQE VSFNCIDEPS RCYFHDGDGV CEEFEQKTSI KDCGVYTPQG FLDQWASNAS VSHQDQQCPG WV IIGQPAA SQVCRTKVID LSEGISQHAW YPCTISYPYS QLAQTTFWLR AYFSQPMVAA AVIVHLVTDG TYYGDQKQET ISV QLLDTK DQSHDLGLHV LSCRNNPLII PVVHDLSQPF YHSQAVRVSF SSPLVAISGV ALRSFDNFDP VTLSSCQRGE TYSP AEQSC VHFACEKTDC PELAVENASL NCSSSDRYHG AQCTVSCRTG YVLQIRRDDE LIKSQTGPSV TVTCTEGKWN KQVAC EPVD CSIPDHHQVY AASFSCPEGT TFGSQCSFQC RHPAQLKGNN SLLTCMEDGL WSFPEALCEL MCLAPPPVPN ADLQTA RCR ENKHKVGSFC KYKCKPGYHV PGSSRKSKKR AFKTQCTQDG SWQEGACVPV TCDPPPPKFH GLYQCTNGFQ FNSECRI KC EDSDASQGLG SNVIHCRKDG TWNGSFHVCQ EMQGQCSVPN ELNSNLKLQC PDGYAIGSEC ATSCLDHNSE SIILPMNV T VRDIPHWLNP TRVERVVCTA GLKWYPHPAL IHCVKGCEPF MGDNYCDAIN NRAFCNYDGG DCCTSTVKTK KVTPFPMSC DLQGDCACRD PQAQEHSRKD LRGYSHG |
-Macromolecule #3: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 60.1 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.7000000000000001 µm |
Sample stage | Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |