Distel B.: Functional genomics of Eukaryotes

Research will continue to focus on how protein function is regulated by ubiquitination. To carry out this work my lab uses a variety of biochemical, molecular biological and cell biological techniques including two-hybrid, protein-protein interaction assays and proteomics. In addition, we have established robust in vitro and in vivo ubiquitination assays. Of special interest is the function of the ubiquitin protein ligase E6AP that is deficient in patients with Angelman Syndrome (collaboration with prof. Elgersma, Erasmus MC). We have previously identified a number of E6AP targets and showed that they bind to distinct regions in E6AP where many missense mutations are found in the UBE3A gene. We will investigate if these proteins are the critical targets in these AS patients by testing the effect of the AS mutations on protein binding, ubiquitination and in vivo function. Recently, we obtained evidence that E6AP activity can be modulated by external factors. We will not only perform a genetic screen to identify novel cellular activators of E6AP, but also develop an in vitro assay that can be used to identify small molecules that can activate E6AP. Such molecules could be of high
therapeutic value for AS patients carrying missense mutations. Themes: Infection and Immunity and Metabolic Disorders