8d8o

Cryo-EM structure of substrate unbound PAPP-A

Structural highlights

8d8o is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.35Å
Ligands:	ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PAPP1_HUMAN Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF. Cleavage of IGFBP-4 is dramatically enhanced by the presence of IGF, whereas cleavage of IGFBP-5 is slightly inhibited by the presence of IGF.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-A(BP5)) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans-dimerization. We further demonstrate that PAPP-A trans-dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity.

Structure of the PAPP-A(BP5) complex reveals mechanism of substrate recognition.,Judge RA, Sridar J, Tunyasuvunakool K, Jain R, Wang JCK, Ouch C, Xu J, Mafi A, Nile AH, Remarcik C, Smith CL, Ghosh C, Xu C, Stoll V, Jumper J, Singh AH, Eaton D, Hao Q Nat Commun. 2022 Sep 20;13(1):5500. doi: 10.1038/s41467-022-33175-2. PMID:36127359^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, Yates JR 3rd, Conover CA. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3149-53. PMID:10077652
↑ Overgaard MT, Haaning J, Boldt HB, Olsen IM, Laursen LS, Christiansen M, Gleich GJ, Sottrup-Jensen L, Conover CA, Oxvig C. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000 Oct 6;275(40):31128-33. PMID:10913121 doi:https://dx.doi.org/10.1074/jbc.M001384200
↑ Laursen LS, Overgaard MT, Soe R, Boldt HB, Sottrup-Jensen L, Giudice LC, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett. 2001 Aug 24;504(1-2):36-40. PMID:11522292
↑ Judge RA, Sridar J, Tunyasunvunakool K, Jain R, Wang JCK, Ouch C, Xu J, Mafi A, Nile AH, Remarcik C, Smith CL, Ghosh C, Xu C, Stoll V, Jumper J, Singh AH, Eaton D, Hao Q. Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition. Nat Commun. 2022 Sep 20;13(1):5500. doi: 10.1038/s41467-022-33175-2. PMID:36127359 doi:https://dx.doi.org/10.1038/s41467-022-33175-2

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, Yates JR 3rd, Conover CA. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3149-53. PMID:10077652

[2] Overgaard MT, Haaning J, Boldt HB, Olsen IM, Laursen LS, Christiansen M, Gleich GJ, Sottrup-Jensen L, Conover CA, Oxvig C. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000 Oct 6;275(40):31128-33. PMID:10913121 doi:https://dx.doi.org/10.1074/jbc.M001384200

[3] Laursen LS, Overgaard MT, Soe R, Boldt HB, Sottrup-Jensen L, Giudice LC, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett. 2001 Aug 24;504(1-2):36-40. PMID:11522292

[4] Judge RA, Sridar J, Tunyasunvunakool K, Jain R, Wang JCK, Ouch C, Xu J, Mafi A, Nile AH, Remarcik C, Smith CL, Ghosh C, Xu C, Stoll V, Jumper J, Singh AH, Eaton D, Hao Q. Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition. Nat Commun. 2022 Sep 20;13(1):5500. doi: 10.1038/s41467-022-33175-2. PMID:36127359 doi:https://dx.doi.org/10.1038/s41467-022-33175-2

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8d8o

Cryo-EM structure of substrate unbound PAPP-A

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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