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SUMMARY:Ubiquitin E3 ligase activity-based profiling: from Parkin to the i
 mpalpable
DTSTART:20181016T171500
DTEND:20181016T181500
DTSTAMP:20260406T171710Z
UID:c595d9b3d6221e03f6c30503cdd723c5a05b4f33bbdd70e931fe7a5f
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Satpal Virdee (University of Dundee)\n\nActivity-based p
 robes (ABPs) provide a direct and substrate-independent measure of enzyme 
 activity. We have developed ABPs for the Homologous to E6AP Carboxy Termin
 us (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 ac
 tivation mechanism of the Parkinson’s disease-associated E3 Parkin. We a
 re exploring the application of ABP profiling to patient samples for asses
 sment of disease predisposition and the presence of unknown regulatory fac
 tors. We have recently interfaced the ABP technology with mass spectrometr
 y granting us agnostic and parallelised profiling of HECT/RBR E3 activity 
 across an entire proteome. This enables HECT/RBR E3 function studies acros
 s an almost limitless number of sample types and conditions. It also has g
 reat utility for drug discovery and the discovery of novel E3 family membe
 rs. I will describe the biochemical and structural characterisation of a n
 ovel 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 deg
 eneration and is a candidate therapeutic target for treating a range of ne
 urological conditions. Strikingly\, the RCR has an unprecedented mechanism
  of action and lacks activity towards conventional lysine substrates. Inst
 ead\, the RCR is endowed with esterification activity with selectivity for
  threonine. This discovery represents a new paradigm in ubiquitin modifica
 tion placing emphasis on the cellular function of non-lysine ubiquitinatio
 n.\n\nStanley et al.\, 2015. ACS Chem Biol 10\, 1542–1554.\nPao et al.\,
  2016. Nature Chemical Biology 12\, 324–331.\nPao et al.\, 2018. Nature 
 556\, 381–385.\n 
LOCATION:BCH 2218 https://plan.epfl.ch/?room==BCH%202218
STATUS:CONFIRMED
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