Research SummaryUnderstanding the structural basis of the substrate and the E2 specificities of ubiquitin E3 ligases
Post-translational modification of proteins via conjugation of ubiquitin or ubiquitin like proteins (UbLs) play critical roles in eukaryotic biology including protein degradation, transcription regulation, DNA repair, viral infection and immune response. Ubiquitination occurs via a cascade of enzymatic reactions involving the activating enzyme (E1), conjugating enzymes (E2) and ubiquitin ligases (E3s). E3 ligases confer substrate specificity to the process via selective interaction with the latter. They also dictate the topology of the modification by choosing their specific E2 partner(s).
Specificity of ubiquitin modifications,like any other biochemical reactions,is crucial ineliciting the desired biological response. In order to understand the molecular determinants of these specificities we plan tostudy a number of ubiquitin E3 ligases involved in diverse cellular pathways using an interdisciplinary approach. We plan to elucidate atomic resolution structures of these E3s in complex with their biological substrate and the cognate E2 enzyme(s) to understand the molecular basis of the substrate and the E2 specificity of these E3s. Such structures coupled with detailed biochemical, biophysical experiments and in vivo validation would provide us with a deeper insight into the ubiquitination machinery and also help to understand the commonalities and the differences that exist between different ubiquitination pathways.
Figure Legend: Crystal structures of two E3 ligases (depicted in green) in complex with their cognate E2 partners (salmon) and Ubiquitin (blue).