Ubiquitin E3 ligase activity-based profiling: from Parkin to the impalpable


Event details

Date 16.10.2018
Hour 17:1518:15
Speaker Prof. Satpal Virdee (University of Dundee)
Category Conferences - Seminars

Activity-based probes (ABPs) provide a direct and substrate-independent measure of enzyme activity. We have developed ABPs for the Homologous to E6AP Carboxy Terminus (HECT) and RING-between-RING (RBR) ubiquitin E3 ligase (E3) subtypes. I will discuss how we used these ABPs to gain insights into the cellular activation mechanism of the Parkinson’s disease-associated E3 Parkin. We are exploring the application of ABP profiling to patient samples for assessment of disease predisposition and the presence of unknown regulatory factors. We have recently interfaced the ABP technology with mass spectrometry granting us agnostic and parallelised profiling of HECT/RBR E3 activity across an entire proteome. This enables HECT/RBR E3 function studies across an almost limitless number of sample types and conditions. It also has great utility for drug discovery and the discovery of novel E3 family members. I will describe the biochemical and structural characterisation of a novel class of E3 we have identified using this technology we term the RING-Cys-Relay (RCR) E3. The RCR is a positive regulator of Wallerian axon degeneration and is a candidate therapeutic target for treating a range of neurological conditions. Strikingly, the RCR has an unprecedented mechanism of action and lacks activity towards conventional lysine substrates. Instead, the RCR is endowed with esterification activity with selectivity for threonine. This discovery represents a new paradigm in ubiquitin modification placing emphasis on the cellular function of non-lysine ubiquitination.

Stanley et al., 2015. ACS Chem Biol 10, 1542–1554.
Pao et al., 2016. Nature Chemical Biology 12, 324–331.
Pao et al., 2018. Nature 556, 381–385.

Practical information

  • General public
  • Free


  • Prof. Beat Fierz


  • Marie Munoz