Occasional auto‐modification of ubiquitin ligases typically leads to their proteasomal destruction, but new findings published in The EMBO Journal now show that in the case of Rsp5/Nedd4, auto‐ubiquitylation instead triggers oligomerization and concomitant reduction of ligase activity. This novel mechanism therefore creates silenced ligases that remain poised for reactivation.
See also: I Attali et al (February 2017)
It is well known that protein kinases and phosphatases may dynamically regulate enzyme activity through cycles of protein phosphorylation and de‐phosphorylation. There are approximately 600 protein kinases identified in the human proteome, which is interestingly roughly equivalent to the known number of human ubiquitin ligases (aka E3 enzymes), the enzymes responsible for transfer of the highly conserved, 76 amino acid protein ubiquitin onto lysine residues of protein substrates in eukaryotic cells (Kleiger & Mayor, 2014). It therefore appears surprising that protein ubiquitylation, at least so far, has not yet been found to play similar roles in reversible control of enzyme activity. However, thanks to the hard work of Attali and colleagues (Attali et al, 2017), this belief may be about to change.
Attali et al (2017) provide major new insights into the mechanism regulating the Nedd4 family of ubiquitin ligases. These important enzymes control a myriad of cellular functions including intracellular trafficking and endocytosis, and their amino acid sequences are highly conserved from yeast to humans. In fact, the activity of the yeast Nedd4 ortholog Rsp5 is essential for viability of this …
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