University of Dundee

Structural basis for substrate recognition by the RNF4 ubiquitin E3 ligase

Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via athirster bond. SUMO-targeted ubiquitin ligases (STUbLs) are a conserved family of proteins that target SUMO-modified proteins for ubiquitylation, as typified by RING finger protein 4 (RNF4) in mammals. RNF4 has a C-terminal RING domain required for ubiquitin E3 ligase activity, while four tandem SIMs located in the N-terminal region provide specificity for binding to its substrate, poly-SUMO chains.  Recently we established the mechanism by which the RING activates the ubiquitin loaded E2 for catalysis (Plechanovova et al., 2012) however the mechanism by which the polySUMO substrate is recognised by the N-terminal region of RNF4 has yet to be established. The objective of the proposed project will be to use structural and biochemical approaches to determine how the multiple SIMs of RNF4 recognise the SUMO chain.

References

  1. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Plechanovová A, Jaffray EG, Tatham MH, Naismith JH, Hay RT Nature. 2012 Sep 6;489(7414):115-20. doi: 10.1038/nature11376. PMID:22842904 (Read online)