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SUMMARY:Structural basis of protein PARylation-dependent ubiquitination - 
 Rachel Klevit\, University of Washington
DTSTART:20140424T151500Z
DTEND:20140424T170000Z
UID:TALK49163@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:Protein poly(ADP-ribosyl)ation (PARylation) plays a role in di
 verse cellular processes such as DNA repair\, transcription\, Wnt signalin
 g\, and cell death. Recent studies have shown that PARylation serves as a 
 signal for the polyubiquitination and degradation of several critical regu
 latory proteins\, including Axin and 3BP2. The RING-type E3 ubiquitin liga
 se RNF146 (a.k.a. Iduna) is responsible for PARylation-dependent ubiquitin
 ation (PARdU). Here we provide a structural basis for RNF146 catalyzed PAR
 dU and how PARdU specificity is achieved. Through a combination of X-ray c
 rystallography\, NMR and biochemical analysis\, we found that iso-ADPr\, t
 he smallest internal poly(ADP-ribose) (PAR) structural unit\, functions as
  an allosteric signal that switches the RING domain from a catalytically i
 nactive state to an active one. In the absence of PAR\, the RING domain is
  unable to bind and activate an E2. Binding of PAR/iso-ADPr to both the WW
 E and RING domains induces a major conformational change that creates a fu
 nctional RING structure. Thus RNF146 represents a new mechanistic class of
  RING E3 ligases whose activities are regulated by ligand binding\, which 
 may provide a template for designing inducible protein-degradation systems
 .  How PARdU specificity is achieved and how this is linked to a switchabl
 e RNF146 E3 ubiquitin ligase activity will be also discussed.
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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