The primary role of endosomal/lysosomal system is protein degradation (Turk et al., 2012). In addition to nonspecific proteolysis in the acidic environment of endosomes/lysosomes, proteolytic enzymes cysteine cathepsins also have specific roles, such as the cleavage of collagen by cathepsin K in bone remodeling, the processing of thyroglobulin in the production of thyroid hormones. They are also involved in the progression of tumors and in the activation of viruses such as SARS-CoV-2 and Ebola. Because of their specific physiological and pathological functions, cysteine cathepsins are important targets for drug discovery.
Our recent analysis of proteolytic degradation of cell lysates by cysteine cathepsins K, V, B, L, S and F revealed about 30,000 cleavage sites (Tusar et al.,2023). The analysis was carried out by SAPS-ESI (“Statistical approach to the specific interaction peptide substrate – enzyme”) software platform. The analysis includes 941 cleavages of a single protein which were cleaved only once (Tušar et al., 2023). We hypothesize that many of these still unexplored single cleavages may be of physiological importance, some of them may indicate links to cancer. The substrates included, for example, transcription factors with cleavages at the sites that bind DNA (Li et al., 2016) or proteins cleaved at the sites where kinases perform phosphorylation (Lolli et al., 2012).
The aim of this research project will be to confirm the potential new roles of cathepsins.
References
- V. Turk et al., Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et biophysica acta 1824, 68-88 (2012).
- Tušar L., Loboda J., Turk D. et al., Proteomic data and structure analysis combined reveal interplay of structural rigidity and flexibility on selectivity of cysteine cathepsins. Communications biology 6, 450 (2023).
- J. Li et al., Structural basis for DNA recognition by STAT6. Proceedings of the National Academy of Sciences of the United States of America 113, 13015-13020 (2016).
- G. Lolli, L. A. Pinna, R. Battistutta, Structural determinants of protein kinase CK2 regulation by autoinhibitory polymerization. ACS chemical biology 7, 1158-1163 (2012).