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 biologi cal role is not well established. IDE has highly selective substrate s pecificity. It degrades insulin, glucagon, atrial natriuretic peptide, transforming growth factor a but does not act on related hormones and growth factors. The structural properties determining whether a pepti de is an IDE substrate are essentially unknown, The reported cleavage sites are not consistent with simple peptide-bond recognition and it w as proposed that IDE recognizes in its substrates some elements of ter tiary structure. We noticed that although IDE substrates are functiona lly unrelated, the majority of them share a specific property, an abil ity to form under certain conditions amyloid fibrils, Utilizing the re sidue pattern recognition procedure, this study reveals a common motif in the sequences of IDE substrates, HNHHHPSH, where H is wholly or pa rtly 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 seq uence motif predetermines a structure recognized by IDE, The identifie d motif appears to be essentially the same as the proposed earlier con sensus sequence for amyloid-forming peptides [Turnell and Finch, J, Mo l. Biol, 227 (1992) 1205-1223]. The study suggests that IDE may play a role in elimination of potentially toxic amyloidogenic peptides. (C) 1998 Federation of European Biochemical Societies.