Identification of the cleavage sites of transforming growth factor alpha by insulin-degrading enzymes

Biochim Biophys Acta. 1997 Apr 4;1338(2):207-14. doi: 10.1016/s0167-4838(96)00202-6.


Insulin-degrading enzyme (IDE) is a sulfhydryl-dependent metalloproteinase with a zinc binding site unique to a new class of proteinases. The enzyme is relatively specific for a number of hormones/growth factors, such as insulin, atrial natriuretic peptide, IGF-II, and proinsulin. In this study we have identified the amino-acid bonds cleaved by IDE in transforming growth factor-alpha. High-performance liquid chromatography was used to separate the peptides generated by the degradation of 125I-TGF-alpha. The peptides were then submitted to sequential Edman degradation to determine the peptide bond broken. Cleavage sites were found at amino acids, 10-11 (Asp-Ser), 25-26 (Val-Gln), 28-29 (Asp-Lys), and 30-31 (Pro-Ala). In agreement with studies of cleavage sites of other hormones by this enzyme, no clear amino-acid specificity was seen. However, examination of the sites on a three-dimensional model of TGF-alpha suggest the primary mechanism used by IDE for determining cleavage sites is the tertiary structure of the substrate.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Insulysin / metabolism*
  • Peptide Mapping
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Substrate Specificity
  • Transforming Growth Factor alpha / metabolism*


  • Transforming Growth Factor alpha
  • Insulysin