A Remodelled Protease That Cleaves Phosphotyrosine Substrates

Proteases are the largest family of enzymes in the human genome and play central roles in a wide range of physiological processes.1 To carry out these diverse functions, proteolytic enzymes have evolved highly tuned substrate specificities that allow them to degrade specific cellular proteins in response to appropriate signals. For many proteases, this specificity is encoded by the amino acid sequence of the polypeptide substrate surrounding the bond that is cleaved (the scissile bond). For example, trypsin recognizes basic residues such as lysine or arginine, and a great diversity of such substrate preferences has been described.2,3 Remarkably, the substrate specificity of known proteases is limited to recognition of the 20 proteogenic (unmodified) amino acids: no protease has been shown to preferentially cleave its substrates adjacent to a site of post-translational modification, such as phosphorylation. Such enzymes would potentially find widespread application either a