Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme.
Insulin-degrading enzyme (IDE) is an evolutionarily conserved neutral thiol metalloprotease expressed in all mammalian tissues whose biological role is not well established. IDE has highly selective substrate specificity. It degrades insulin, glucagon, atrial natriuretic peptide, transforming growth factor alpha but does not act on related hormones and growth factors. The structural properties determining whether a peptide is an IDE substrate are essentially unknown. The reported cleavage sites are not consistent with simple peptide-bond recognition and it was proposed that IDE recognizes in its substrates some elements of tertiary structure. We noticed that although IDE substrates are functionally unrelated, the majority of them share a specific property, an ability to form under certain conditions amyloid fibrils. Utilizing the residue pattern recognition procedure, this study reveals a common motif in the sequences of IDE substrates, HNHHHPSH, where H is wholly or partly hydrophobic character, N is small and neutral, P is polar, and S is polar and/or small amino acid residue. It is proposed that this sequence motif predetermines a structure recognized by IDE. The identified motif appears to be essentially the same as the proposed earlier consensus sequence for amyloid-forming peptides [Turnell and Finch, J. Mol. Biol. 227 (1992) 1205-1223]. The study suggests that IDE may play a role in elimination of potentially toxic amyloidogenic peptides.
Kurochkin
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Chugai Research Institute for Molecular Medicine, Inc., Niihari, Ibaraki, Japan. igork@tk.chugai-pharm.co.jp
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D007339:Insulysin / Q000737:chemistry*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry*; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D000682:Amyloid; D009842:Oligopeptides; D007339:Insulysin