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PhD B. Distel

Position
Associate Professor
Main activities
Education, Research
Specialisation
Biochemistry and molecular biology
Focus of research

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.

 

Key publications
  • Williams Chris, van den Berg Marlene, Panjikar Santosh, Stanley Will A., Distel Ben, Wilmanns Matthias Insights into ubiquitin-conjugating enzyme/co-activator interactions from the structure of the Pex4p:Pex22p complex EMBO journal 2012;31 (2):391-402 [PubMed]
  • Williams Chris, van den Berg Marlene, Stanley Will A., Wilmanns Matthias, Distel Ben A disulphide bond in the E2 enzyme Pex4p modulates ubiquitin-conjugating activity Scientific reports 2013;3:2212-(6 p.) [PubMed]
  • Silva-Santos Sara, van Woerden Geeske M., Bruinsma Caroline F., Mientjes Edwin, Jolfaei Mehrnoush Aghadavoud, Distel Ben, Kushner Steven A., Elgersma Ype Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model Journal of clinical investigation 2015;125 (5):2069-2076 [PubMed]
  • Verschueren Erik, Spiess Matthias, Gkourtsa Areti, Avula Teja, Landgraf Christiane, Mancilla Victor Tapia, Huber Aline, Volkmer Rudolf, Winsor Barbara, Serrano Luis, Hochstenbach Frans, Distel Ben Evolution of the SH3 Domain Specificity Landscape in Yeasts PLoS ONE 2015;10 (6):e0129229 [PubMed]
  • Gkourtsa Areti, van den Burg Janny, Strijbis Karin, Avula Teja, Bijvoets Sietske, Timm Dave, Hochstenbach Frans, Distel Ben Identification and characterization of Rvs162/Rvs167-3, a novel N-BAR heterodimer in the human fungal pathogen Candida albicans Eukaryotic cell 2015;14 (2):182-193 [PubMed]
All Publications
Research programmes

PhD B. Distel (Functional genomics of Eukaryotes)

Research will continue to focus on the function of the ubiquitin protein ligase E6AP that is deficient in patients with Angelman Syndrome. About 10% of the AS patients harbor missense mutations in the coding region of the UBE3A gene. For most of these mutations it is currently unclear how these mutations disrupt E6AP function. We have introduced these AS missense mutations in the UBE3A gene and will test the effect of these mutations on target protein binding, ubiquitin protein ligase activity, stability and in vivo function. Recently, we obtained evidence that E6AP activity can be modulated by external factors. We have constructed tailored brain cDNA libraries that will be used in genetic screens to identify novel cellular activators of E6AP. Finally, we have converted the bacterial ubiquitination system to a proteome-wide method that allows us to screen a brain cDNA expression library for proteins that are ubiquitinated by E6AP. These systematic approaches aimed at identification and characterization of E6AP targets and understanding how E6AP activity is regulated will not only provide fundamental insight into the pathophysiology of AS but may also reveal potential targets for therapeutic strategies.

 

Themes:  Infection and Immunity  and Metabolic Disorders

 

Others
BEng M. van den Berg
J. van den Burg