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- PDB-8sl1: Cryo-EM structure of PAPP-A2 -

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Basic information

Entry
Database: PDB / ID: 8sl1
TitleCryo-EM structure of PAPP-A2
ComponentsPappalysin-2
KeywordsHYDROLASE / PEPTIDE BINDING PROTEIN / Protease / zinc binding / growth factor signaling / peptide binding
Function / homology
Function and homology information


protein metabolic process / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / bone morphogenesis / response to salt stress / regulation of cell growth / metalloendopeptidase activity / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cell surface receptor signaling pathway / apical plasma membrane ...protein metabolic process / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / bone morphogenesis / response to salt stress / regulation of cell growth / metalloendopeptidase activity / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cell surface receptor signaling pathway / apical plasma membrane / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region
Similarity search - Function
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 / LNR domain / Notch domain / Domain found in Notch and Lin-12 ...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 / LNR domain / 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 / Metallopeptidase, catalytic domain superfamily / Fibronectin type III superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsJudge, R.A. / Stoll, V.S. / Eaton, D. / Hao, Q. / Bratkowski, M.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Chem / Year: 2023
Title: Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition.
Authors: Janani Sridar / Amirhossein Mafi / Russell A Judge / Jun Xu / Kailyn A Kong / John C K Wang / Vincent S Stoll / Georgios Koukos / Reyna J Simon / Dan Eaton / Matthew Bratkowski / Qi Hao /
Abstract: Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor ...Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling. The structures of homodimeric PAPP-A in complex with IGFBP5 anchor peptide, and inhibitor proteins STC2 and proMBP have been recently reported. Here, we present the single-particle cryo-EM structure of the monomeric, N-terminal LG, MP, and the M1 domains (with the exception of LNR1/2) of human PAPP-A2 to 3.13 Å resolution. Our structure together with functional studies provides insight into a previously reported patient mutation that inactivates PAPP-A2 in a distal region of the protein. Using a combinational approach, we suggest that PAPP-A2 recognizes IGFBP5 in a similar manner as PAPP-A and show that PAPP-A2 cleaves IGFBP5 less efficiently due to differences in the M2 domain. Overall, our studies characterize the cleavage mechanism of IGFBP5 by PAPP-A2 and shed light onto key differences with its paralog PAPP-A.
History
DepositionApr 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Pappalysin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,0516
Polymers174,2601
Non-polymers7915
Water181
1


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

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Pappalysin-2 / / Pregnancy-associated plasma protein A2 / PAPP-A2 / Pregnancy-associated plasma protein E1 / PAPP-E


Mass: 174259.766 Da / Num. of mol.: 1 / Fragment: UNP residues 235-1791
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAPPA2, PLAC3 / Production host: Homo sapiens (human)
References: UniProt: Q9BXP8, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases

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Sugars , 2 types, 2 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 4 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Ca
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: PAPP-A2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
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: 400 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 FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: CTFFIND / Version: 4.1.10 / Category: CTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0046786
ELECTRON MICROSCOPYf_angle_d0.5759258
ELECTRON MICROSCOPYf_dihedral_angle_d4.184922
ELECTRON MICROSCOPYf_chiral_restr0.0421016
ELECTRON MICROSCOPYf_plane_restr0.0061217

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