8a7d | pdb_00008a7d

Partial dimer complex of PAPP-A and its inhibitor STC2

Structural highlights

8a7d is a 3 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 3.06Å
Ligands:	CA, NAG, 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

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 A) 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.

Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism.,Kobbero SD, Gajhede M, Mirza OA, Kloverpris S, Kjaer TR, Mikkelsen JH, Boesen T, Oxvig C Nat Commun. 2022 Oct 18;13(1):6084. doi: 10.1038/s41467-022-33698-8. PMID:36257932^[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
↑ Kobbero SD, Gajhede M, Mirza OA, Kloverpris S, Kjaer TR, Mikkelsen JH, Boesen T, Oxvig C. Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Nat Commun. 2022 Oct 18;13(1):6084. doi: 10.1038/s41467-022-33698-8. PMID:36257932 doi:https://dx.doi.org/10.1038/s41467-022-33698-8

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] Kobbero SD, Gajhede M, Mirza OA, Kloverpris S, Kjaer TR, Mikkelsen JH, Boesen T, Oxvig C. Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Nat Commun. 2022 Oct 18;13(1):6084. doi: 10.1038/s41467-022-33698-8. PMID:36257932 doi:https://dx.doi.org/10.1038/s41467-022-33698-8

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8a7d | pdb_00008a7d

Partial dimer complex of PAPP-A and its inhibitor STC2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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