Sequential Poly-ubiquitylation by Specialized Conjugating Enzymes Expands the Versatility of a Quality Control Ubiquitin Ligase

Annika Weber, Itamar Cohen, Oliver Popp, Gunnar Dittmar, Yuval Reiss, Thomas Sommer*, Tommer Ravid, Ernst Jarosch

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

The Doa10 quality control ubiquitin (Ub) ligase labels proteins with uniform lysine 48-linked poly-Ub (K48-pUB) chains for proteasomal degradation. Processing of Doa10 substrates requires the activity of two Ub conjugating enzymes. Here we show that the non-canonical conjugating enzyme Ubc6 attaches single Ub molecules not only to lysines but also to hydroxylated amino acids. These Ub moieties serve as primers for subsequent poly-ubiquitylation by Ubc7. We propose that the evolutionary conserved propensity of Ubc6 to mount Ub on diverse amino acids augments the number of ubiquitylation sites within a substrate and thereby increases the target range of Doa10. Our work provides new insights on how the consecutive activity of two specialized conjugating enzymes facilitates the attachment of poly-Ub to very heterogeneous client molecules. Such stepwise ubiquitylation reactions most likely represent a more general cellular phenomenon that extends the versatility yet sustains the specificity of the Ub conjugation system.

Original languageAmerican English
Pages (from-to)827-839
Number of pages13
JournalMolecular Cell
Volume63
Issue number5
DOIs
StatePublished - 1 Sep 2016

Bibliographical note

Funding Information:
We thank the members of the G.D., T.R., and T.S. groups and Jasmin Schlotthauer for support and fruitful discussions. Mark Hochstrasser (Yale University School of Medicine) and Cynthia Wolberger (Johns Hopkins University School of Medicine) are acknowledged for providing plasmids and yeast strains. Our work is generously supported by Deutsche Forschungsgemeinschaft (projects HO 2541/4-1, SO 271/6-1, and SFB 740/TP B05) and by the Israel Science Foundation (grant 786/08).

Publisher Copyright:
© 2016 Elsevier Inc.

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