Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase

J Biol Chem. 2001 Jun 15;276(24):21849-53. doi: 10.1074/jbc.M102191200. Epub 2001 Mar 22.


A novel metalloproteinase with similarity to pregnancy-associated plasma protein-A (PAPP-A), which we denoted PAPP-A2, has been identified. Through expression in mammalian cells we showed that recombinant PAPP-A2 polypeptide of 1558 residues resulted from processing of a 1791-residue prepro-protein. Unlike PAPP-A, PAPP-A2 migrated as a monomer (of 220 kDa) in non-reducing SDS-polyacrylamide gel electrophoresis. The prepro-parts of PAPP-A2 and PAPP-A are not homologous, but mature PAPP-A2 shares 45% of its residues with PAPP-A. Because PAPP-A specifically cleaves insulin-like growth factor-binding protein (IGFBP)-4, one of six known modulators of IGF-I and -II, we looked for a possible PAPP-A2 substrate among the members of this family. We showed that PAPP-A2 specifically cleaved IGFBP-5 at one site, between Ser-143 and Lys-144. In contrast to the cleavage of IGFBP-4 by PAPP-A that strictly requires the presence of IGF, the cleavage of IGFBP-5 by PAPP-A2 was IGF-independent. Recent data firmly establish PAPP-A and IGFBP-4 as an important functional pair in several systems. Because of its close relationship with PAPP-A, both structurally and functionally, PAPP-A2 is a likely candidate IGFBP-5 proteinase in many tissues and conditioned media where IGFBP-5 proteolysis has been reported.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • DNA Primers
  • Databases, Factual
  • Endopeptidases / chemistry*
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism
  • Enzyme Precursors / chemistry
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Expressed Sequence Tags
  • Humans
  • Insulin-Like Growth Factor Binding Protein 4 / metabolism
  • Metalloendopeptidases / chemistry*
  • Metalloendopeptidases / genetics*
  • Molecular Sequence Data
  • Molecular Weight
  • Pregnancy Proteins / chemistry*
  • Pregnancy Proteins / genetics*
  • Pregnancy Proteins / metabolism
  • Pregnancy-Associated Plasma Protein-A / chemistry
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid


  • DNA Primers
  • Enzyme Precursors
  • Insulin-Like Growth Factor Binding Protein 4
  • Pregnancy Proteins
  • Recombinant Proteins
  • Endopeptidases
  • PAPPA2 protein, human
  • Metalloendopeptidases
  • Pregnancy-Associated Plasma Protein-A

Associated data

  • GENBANK/AF311940