Summary
In this project we will combine the strengths of affinity-purification mass spectrometry with high-resolution peptide separation and MS identification to study in detail a few systems that are at the core of this theme 2. These protein assemblies are the mammalian proteasome machinery, the cAMP dependent protein kinase A and the calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II. These systems are biologically not directly linked, but chemical proteomics methods developed in this project can be well applied to both these systems.
The proteasome project is directly supported by NPCII funding and brings together our considerable array of chemical biology technology we have amassed over the years, and will benefit from the input given by partners in the theme. Some fundamental questions we will address are the heterogeneity of proteasome assemblies, the role of post-translational modification in proteasome functioning and degradation of the proteasome itself. We will validate inhibitors to monitor proteasome functioning in cancer, with possible new directions for drug development as a result. Next to more in-depth knowledge about  the diversity in function and composition of the proteasome the data will aid research aimed at the development of more specific inhibitors to be used as chemotherapeutics.