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Area of Science:

  • Biochemistry
  • Evolutionary Biology
  • Enzymology

Background:

  • Pappalysin (PAPP-A) and PAPP-A2 are metalloproteinases regulating the insulin-like growth factor (IGF) system by cleaving IGF binding proteins (IGFBPs).
  • Stanniocalcin-1 and -2 (STC1/STC2) inhibit pappalysins, forming the STC-PAPP-A-IGFBP-IGF axis.
  • Understanding pappalysin evolution and function is crucial, especially as PAPP-A is an emerging drug target.

Purpose of the Study:

  • To investigate the evolutionary presence and functional conservation of pappalysins across the animal kingdom.
  • To identify novel pappalysin groups and their relationship to known vertebrate forms.
  • To explore potential functions of pappalysins beyond the established IGF system.

Main Methods:

  • Utilized homology searches and phylogenetic analyses to identify and classify pappalysin enzymes.
  • Examined conserved domain architecture and functional motifs across metazoan pappalysins.
  • Compared the evolutionary origins of PAPP-A, PAPP-A2, and invertebrate pappalysins (invPAPP-A).

Main Results:

  • Pappalysins are widespread across metazoans, with three distinct groups identified: PAPP-A, PAPP-A2, and invPAPP-A.
  • PAPP-A and PAPP-A2 originated from gene duplication in early vertebrate evolution.
  • Metazoan pappalysins share conserved domain architecture and functional motifs.
  • invPAPP-A functions independently of IGFBPs, indicating potential novel substrates and roles.

Conclusions:

  • The pappalysin family is ancient and broadly conserved in animals, with distinct evolutionary trajectories for vertebrate and invertebrate forms.
  • Conserved functional elements suggest a fundamental role for pappalysins, while invPAPP-A highlights potential undiscovered functions.
  • Further research into non-IGFBP substrates of pappalysins is warranted, particularly given PAPP-A's status as a drug target.