In the last ten years my research group has focused on the role of protein ubiquitination in disease. To unravel the function of protein ubiquitination in disease development we use a variety of biochemical, molecular biological and cell-biological techniques including yeast two-hybrid, protein-protein interaction assays and proteomics. In 2005 we discovered a novel type of ubiquitination that targets a cysteine residue in the substrate protein. Since then my group has made other important contributions to the ubiquitin field among which the identification and characterization of the RING E3 ligase involved in the ubiquitination of the peroxisomal import receptor and establishing a novel mechanism of E2 enzyme regulation that involves binding of a co-activator protein. Since 2010 we use our expertise on protein ubiquitination to study the role of this protein modification in Angelman Syndrome, a severe neurological disorder caused by mutations in the UBE3A gene encoding the ubiquitin protein ligase E6AP (collaboration with prof. Elgersma, Erasmus MC). To carry out this work we have established in vitro and cellular ubiquitination assays, including a recently developed system in which we have reconstituted E6AP-dependent target ubiquitination in bacteria. Protein-protein interaction screens have led to the identification of several E6AP-interacting proteins. We are using our battery of in vitro and cellular assays to establish the in vivo function of these E6AP targets and determine their contribution to AS pathology.