Editors' ChoicePosttranslational modification

Targeting Ubiquitination with PARylation

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Sci. Signal.  21 Feb 2012:
Vol. 5, Issue 212, pp. ec58
DOI: 10.1126/scisignal.2002972

The covalent attachment of ubiquitin to target proteins by ubiquitin E3 ligases may affect the degradation, localization, or activity of the modified proteins. It is not always clear how E3 ligases are targeted to specific substrates, but poly(ADP-ribosyl)ation (PARylation) of the scaffolding protein and Wnt signaling component axin is required for its polyubiquitination by RNF146. Wang et al. report that PARylation may be a more general mechanism for tagging proteins for ubiquitination. The WWE domain is named for its conserved Trp and Glu residues and is often found in proteins that also have ubiquitin E3 ligase activity, such as RNF146. Wang and colleagues determined that the WWE domain of RNF146 bound specifically to poly(ADP-ribose) (PAR) but not to monomeric ADP-ribose, and structural analysis revealed the residues that constituted the PAR binding motif (PBM). Targeted mutagenesis confirmed the importance of these residues for RNF146 binding to PAR in vitro and for RNF146-mediated degradation of axin in cultured cells. The PBM was conserved in 10 of 11 other human WWE domain–containing E3 ubiquitin ligases analyzed. Four of the WWE domains that contained the conserved residues were tested, and each bound to PAR in vitro; the WWE domain from the protein that did not have the conserved residues did not bind PAR. The authors propose that these ubiquitin ligases are recruited to PARylated targets and that PARylation may be a widespread mechanism of targeting proteins for ubiquitination by those ubiquitin ligases that also contain a WWE domain.

Z. Wang, G. A. Michaud, Z. Cheng, Y. Zhang, T. R. Hinds, E. Fan, F. Cong, W. Xu, Recognition of the iso-ADP-ribose moiety in poly(ADP-ribose) by WWE domains suggests a general mechanism for poly(ADP-ribosyl)ation-dependent ubiquitination. Genes Dev. 26, 235–240 (2012). [Abstract] [Full Text]