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Anion Activation Site Of Insulin-Degrading Enzyme, Nicholas Noinaj, Eun Suk Song, Sonia Bhasin, Benjamin J. Alper, Walter K. Schmidt, Louis B. Hersh, David W. Rodgers

Chemistry & Physics Faculty Publications

Insulin-degrading enzyme (IDE) (insulysin) is a zinc metallopeptidase that metabolizes several bioactive peptides, including insulin and the amyloid β peptide. IDE is an unusual metallopeptidase in that it is allosterically activated by both small peptides and anions, such as ATP. Here, we report that the ATP-binding site is located on a portion of the substrate binding chamber wall arising largely from domain 4 of the four-domain IDE. Two variants having residues in this site mutated, IDE^{K898A,K899A,S901A} and IDE^R429S, both show greatly decreased activation by the polyphosphate anions ATP and PPP_i. IDE^{K898A,K899A,S901A} is also deficient …