Combinatorial degradomics: Precision tools to unveil proteolytic processes in biological systems.

The biological activity of a protein is regulated at many levels ranging from control of transcription and translation to post-translational modifications (PTM). Proteolytic processing is an irreversible PTM generating novel isoforms of a mature protein termed proteoforms. Proteoform dynamics is a major focus of current proteome research, since it has been associated with many pathological conditions. Mass-spectrometry (MS)-based proteomics and PTM-specific enrichment workflows have become the methods of choice to study proteoforms in vitro and in vivo. Here, we give an overview of currently available MS-based degradomics methods and outline how they can be optimally applied to study protease cleavage events. We discuss the advantages and disadvantages of selected approaches and describe state-of-the-art improvements in degradomics technologies. By introducing the concept of combinatorial degradomics, a combination of global discovery degradomics and highly sensitive targeted degradomics, we demonstrate how MS-based degradomics further evolves as a powerful tool in biomedical protease research.