Structural basis of protein PARylation-dependent ubiquitination

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• Rachel Klevit, University of Washington
• Thursday 24 April 2014, 16:15-18:00
• Max Perutz Lecture Theatre, Medical Research Council (MRC) (MRC Laboratory of Molecular Biol.

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Protein poly(ADP-ribosyl)ation (PARylation) plays a role in diverse cellular processes such as DNA repair, transcription, Wnt signaling, and cell death. Recent studies have shown that PARylation serves as a signal for the polyubiquitination and degradation of several critical regulatory proteins, including Axin and 3BP2. The RING -type E3 ubiquitin ligase RNF146 (a.k.a. Iduna) is responsible for PARylation-dependent ubiquitination (PARdU). Here we provide a structural basis for RNF146 catalyzed PARdU and how PARdU specificity is achieved. Through a combination of X-ray crystallography, NMR and biochemical analysis, we found that iso-ADPr, the smallest internal poly(ADP-ribose) (PAR) structural unit, functions as an allosteric signal that switches the RING domain from a catalytically inactive 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 WWE and RING domains induces a major conformational change that creates a functional 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 switchable RNF146 E3 ubiquitin ligase activity will be also discussed.

This talk is part of the MRC LMB Seminar Series series.

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