The protease web

Proteases regulate other proteases directly via cleavage or indirectly via cleavage and the inactivation of protease inhibitors. These proteolytic interactions enable functional cross-talk between proteases and have been well established in proteolytic cascades. In addition, far-reaching interactions beyond classically defined protease cascades have been identified, suggesting a larger network of proteases—the protease web. Protease cross-talk in this network has potentially detrimental effects on protease biology in health and disease. This chapter outlines the evidence for the protease web, its effect on drug discovery and protease substrate identification, and computational approaches for modeling and predicting proteolytic interactions within this network.