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- EMDB-15217: PAPP-A dimer in complex with a dimer of the inhibitor STC2 -

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Basic information

Entry
Database: EMDB / ID: EMD-15217
TitlePAPP-A dimer in complex with a dimer of the inhibitor STC2
Map dataPrimary, sharpened map of PAPP-A dimer with its endogenous inhibitor STC2
Sample
  • Complex: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
    • Complex: PAPP-A
      • Protein or peptide: PAPP-A
    • Complex: Stanniocalcin-2
      • Protein or peptide: STC2
KeywordsMetzincin metalloprotease Inhibitor complex / HYDROLASE
Function / homology
Function and homology information


regulation of hormone biosynthetic process / regulation of store-operated calcium entry / response to vitamin D / negative regulation of multicellular organism growth / decidualization / endoplasmic reticulum unfolded protein response / embryo implantation / Post-translational protein phosphorylation / hormone activity / response to peptide hormone ...regulation of hormone biosynthetic process / regulation of store-operated calcium entry / response to vitamin D / negative regulation of multicellular organism growth / decidualization / endoplasmic reticulum unfolded protein response / embryo implantation / Post-translational protein phosphorylation / hormone 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) / cellular response to hypoxia / response to oxidative stress / endoplasmic reticulum lumen / negative regulation of gene expression / heme binding / perinuclear region of cytoplasm / Golgi apparatus / enzyme binding / endoplasmic reticulum / protein homodimerization activity / extracellular space
Similarity search - Function
Stanniocalcin / Stanniocalcin family
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.05 Å
AuthorsKobbero SD / Oxvig C / Gajhede M / Boesen T
Funding support Denmark, 1 items
OrganizationGrant numberCountry
Danish Council for Independent Research Denmark
CitationJournal: Nat Commun / Year: 2022
Title: Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism.
Authors: Sara Dam Kobberø / Michael Gajhede / Osman Asghar Mirza / Søren Kløverpris / Troels Rønn Kjær / Jakob Hauge Mikkelsen / Thomas Boesen / Claus Oxvig /
Abstract: The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single- ...The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single-particle cryo-electron microscopy (cryo-EM), we here report the structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2 (STC2), neither of which have been reported before. The highest resolution (3.1 Å) was obtained for the STC2 subunit and the N-terminal approximately 1000 residues of the PAPP-A subunit. The 500 kDa 2:2 PAPP-A·STC2 complex is a flexible multidomain ensemble with numerous interdomain contacts. In particular, a specific disulfide bond between the subunits of STC2 and PAPP-A prevents dissociation, and interactions between STC2 and a module located in the very C-terminal end of the PAPP-A subunit prevent binding of its main substrate, IGFBP-4. While devoid of activity towards IGFBP-4, the active site cleft of the catalytic domain is accessible in the inhibited PAPP-A·STC2 complex, as shown by its ability to hydrolyze a synthetic peptide derived from IGFBP-4. Relevant to multiple human pathologies, this unusual mechanism of proteolytic inhibition may support the development of specific pharmaceutical agents, by which IGF signaling can be indirectly modulated.
History
DepositionJun 20, 2022-
Header (metadata) releaseNov 2, 2022-
Map releaseNov 2, 2022-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15217.png

Downloads & links

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Map

FileDownload / File: emd_15217.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary, sharpened map of PAPP-A dimer with its endogenous inhibitor STC2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.19 Å/pix.
x 256 pix.
= 303.6 Å		1.19 Å/pix.
x 256 pix.
= 303.6 Å		1.19 Å/pix.
x 256 pix.
= 303.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.18594 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0385
Minimum - Maximum-0.3111115 - 0.5706505
Average (Standard dev.)0.0012017725 (±0.013350641)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 303.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Raw map of PAPP-A dimer with its endogenous inhibitor STC2

Fileemd_15217_additional_1.map
AnnotationRaw map of PAPP-A dimer with its endogenous inhibitor STC2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A from the raw map

Fileemd_15217_half_map_1.map
AnnotationHalf map A from the raw map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B from the raw map

Fileemd_15217_half_map_2.map
AnnotationHalf map B from the raw 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 : PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer

EntireName: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
Components
  • Complex: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
    • Complex: PAPP-A
      • Protein or peptide: PAPP-A
    • Complex: Stanniocalcin-2
      • Protein or peptide: STC2

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Supramolecule #1: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer

SupramoleculeName: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Inhibited proteolytic complex generated by harvest of serum media, purifying on a nickel column followed by negative affinity purification and size-exclusion chromatography.
Molecular weightTheoretical: 400 KDa

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Supramolecule #2: PAPP-A

SupramoleculeName: PAPP-A / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 / Details: Homodimer Pregnancy-associated plasma protein A
Source (natural)Organism: Homo sapiens (human) / Tissue: ubiquitous / Location in cell: extracellular

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Supramolecule #3: Stanniocalcin-2

SupramoleculeName: Stanniocalcin-2 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2 / Details: Homodimer
Source (natural)Organism: Homo sapiens (human) / Tissue: ubiquitous / Location in cell: extracellular

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Macromolecule #1: PAPP-A

MacromoleculeName: PAPP-A / type: protein_or_peptide / ID: 1
Details: A heterotetrameric complex between the protease PAPP-A dimer and its endogenous inhibitor STC2
Enantiomer: LEVO / EC number: pappalysin-1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EARGATEEPS PPSRALYFSG RGEQLRLRAD LELPRDAFT LQVWLRAEGG QRSPAVITGL YDKCSYISRD RGWVVGIHTI SDQDNKDPRY FFSLKTDRAR QVTTINAHR SYLPGQWVYL AATYDGQFMK LYVNGAQVAT SGEQVGGIFS PLTQKCKVLM L GGSALNHN ...String:
EARGATEEPS PPSRALYFSG RGEQLRLRAD LELPRDAFT LQVWLRAEGG QRSPAVITGL YDKCSYISRD RGWVVGIHTI SDQDNKDPRY FFSLKTDRAR QVTTINAHR SYLPGQWVYL AATYDGQFMK LYVNGAQVAT SGEQVGGIFS PLTQKCKVLM L GGSALNHN YRGYIEHFSL WKVARTQREI LSDMETHGAH TALPQLLLQE NWDNVKHAWS PM KDGSSPK VEFSNAHGFL LDTSLEPPLC GQTLCDNTEV IASYNQLSSF RQPKVVRYRV VNL YEDDHK NPTVTREQVD FQHHQLAEAF KQYNISWELD VLEVSNSSLR RRLILANCDI SKIG DENCD PECNHTLTGH DGGDCRHLRH PAFVKKQHNG VCDMDCNYER FNFDGGECCD PEITN VTQT CFDPDSPHRA YLDVNELKNI LKLDGSTHLN IFFAKSSEEE LAGVATWPWD KEALMH LGG IVLNPSFYGM PGHTHTMIHE IGHSLGLYHV FRGISEIQSC SDPCMETEPS FETGDLC ND TNPAPKHKSC GDPGPGNDTC GFHSFFNTPY NNFMSYADDD CTDSFTPNQV ARMHCYLD L VYQGWQPSRK PAPVALAPQV LGHTTDSVTL EWFPPIDGHF FERELGSACH LCLEGRILV QYASNASSPM PCSPSGHWSP REAEGHPDVE QPCKSSVRTW SPNSAVNPHT VPPACPEPQG CYLELEFLY PLVPESLTIW VTFVSTDWDS SGAVNDIKLL AVSGKNISLG PQNVFCDVPL T IRLWDVGE EVYGIQIYTL DEHLEIDAAM LTSTADTPLC LQCKPLKYKV VRDPPLQMDV AS ILHLNRK FVDMDLNLGS VYQYWVITIS GTEESEPSPA VTYIHGSGYC GDGIIQKDQG EQC DDMNKI NGDGCSLFCR QEVSFNCIDE PSRCYFHDGD GVCEEFEQKT SIKDCGVYTP QGFL DQWAS NASVSHQDQQ CPGWVIIGQP AASQVCRTKV IDLSEGISQH AWYPCTISYP YSQLA QTTF WLRAYFSQPM VAAAVIVHLV TDGTYYGDQK QETISVQLLD TKDQSHDLGL HVLSCR NNP LIIPVVHDLS QPFYHSQAVR VSFSSPLVAI SGVALRSFDN FDPVTLSSCQ RGETYSP AE QSCVHFACEK TDCPELAVEN ASLNCSSSDR YHGAQCTVSC RTGYVLQIRR DDELIKSQ T GPSVTVTCTE GKWNKQVACE PVDCSIPDHH QVYAASFSCP EGTTFGSQCS FQCRHPAQL KGNNSLLTCM EDGLWSFPEA LCELMCLAPP PVPNADLQTA RCRENKHKVG SFCKYKCKPG YHVPGSSRK SKKRAFKTQC TQDGSWQEGA CVPVTCDPPP PKFHGLYQCT NGFQFNSECR I KCEDSDAS QGLGSNVIHC RKDGTWNGSF HVCQEMQGQC SVPNELNSNL KLQCPDGYAI GS ECATSCL DHNSESIILP MNVTVRDIPH WLNPTRVERV VCTAGLKWYP HPALIHCVKG CEP FMGDNY CDAINNRAFC NYDGGDCCTS TVKTKKVTPF PMSCDLQGDC ACRDPQAQEH SRKD LRGYS HG

GENBANK: GENBANK: Q13219

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Macromolecule #2: STC2

MacromoleculeName: STC2 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Cell: Extracellular
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MCAERLGQFM TLALVLATFD PARGTDATNP PEGPQDRSSQ QKGRLSLQNT AEIQHCLVNA GDVGCGVFE CFENNSCEIR GLHGICMTFL HNAGKFDAQG KSFIKDALKC KAHALRHRFG C ISRKCPAI REMVSQLQRE CYLKHDLCAA AQENTRVIVE MIHFKDLLLH ...String:
MCAERLGQFM TLALVLATFD PARGTDATNP PEGPQDRSSQ QKGRLSLQNT AEIQHCLVNA GDVGCGVFE CFENNSCEIR GLHGICMTFL HNAGKFDAQG KSFIKDALKC KAHALRHRFG C ISRKCPAI REMVSQLQRE CYLKHDLCAA AQENTRVIVE MIHFKDLLLH EPYVDLVNLL LT CGEEVKE AITHSVQVQC EQNWGSLCSI LSFCTSAIQK PPTAPPERQP QVDRTKLSRA HHG EAGHHL PEPSSRETGR GAKGERGSKS HPNAHARGRV GGLGAQGPSG SSEWEDEQSE YSDI RR

UniProtKB: Stanniocalcin-2

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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

Concentration0.6 mg/mL
BufferpH: 7.4 / Details: HEPES buffer
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: 1.8 µm / Nominal defocus min: 0.6 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 59.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.05 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 114226
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT

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