The posttranslational modification of lysine residues in proteins with another small protein, ubiquitin, regulates a plethora of fundamental cellular processes. High versatility is achieved since ubiquitin can be ubiquitinated itself at eight different positions, leading to polyubiquitin chains. Cells utilise this repertoire of modifications extensively, and all linkage types can be readily detected in eukaryotic cells.
The best understood ubiquitin polymers are Lys48-linked chains, which target proteins for proteasomal degradation, and Lys63-linked chains, which have important non-degradative functions in cell signalling, endocytosis and the DNA damage response.
The roles of the remaining, atypical polyubiquitin chains are currently less clear, and little is known about the machinery for their specific assembly, about receptors for these signals, and about the enzymes that hydrolyse these chains.
Our work focuses on atypical ubiquitin chains, and we aim to understand their roles in the cell, and reveal how proteins distinguish between the different chain types.
To achieve these aims, we study linkage-specificity in E3 ligases to identify the assembly machineries for atypical chains.
Newly generated atypical chain types are then used as tools to discover linkage-specific ubiquitin binding proteins and deubiquitinases.
Such linkage-specific proteins are then characterised structurally, to understand the molecular basis of linkage-specificity, and functionally, to reveal which cellular processes involve atypical chains.
- Elliott, P.R., Nielsen, S.V., Marco-Casanova, P., Fiil, B.K., Keusekotten, K., Mailand, N., Freund, S.M., Gyrd-Hansen, M. and Komander, D. (2014)
Molecular Basis and Regulation of OTULIN-LUBAC Interaction
Mol Cell 54(3): 335-348
- Mevissen, T.E.T., Hospenthal, M.K., Geurink, P.P., Elliott, P.R., Akutsu, M., Arnaudo, N., Ekkebus, R., Kulathu, Y., Wauer, T., El Oualid F, Freund, S.M.V., Ovaa, H. and Komander, D. (2013)
OTU domain deubiquitinases reveal mechanisms of linkage-specificity and enable ubiquitin chain restriction analysis
Cell 154(1): 169-184
- Keusekotten, K., Elliott, P.R., Glockner, L., Fiil, B.K., Damgaard, R.B., Kulathu, Y., Wauer, T., Hospenthal, M.K., Gyrd-Hansen, M., Krappmann, D., Hofmann, K. and Komander, D. (2013)
OTULIN antagonizes LUBAC signaling by specifically hydrolysing Met1-linked polyubiquitin
Cell 153(6): 1312-1326
- Wauer, T. and Komander, D. (2013)
Structure of the human Parkin ligase domain in an autoinhibited state
EMBO J 32(15): 2099-2112
- Ye, Y., Blaser, G., Horrocks, M.H., Ruedas-Rama, M.J., Ibrahim, S., Zhukov, A.A., Orte, A., Klenerman, D., Jackson, S.E. and Komander D (2012)
Ubiquitin chain conformation regulates recognition and activity of interacting proteins
Nature 492(7428): 266-270
- Kulathu, Y. and Komander, D. (2012)
Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages
Nat Rev Mol Cell Biol 13(8): 508-523
- Komander, D. and Rape, M. (2012)
The Ubiquitin Code
Annual Reviews in Biochemistry 81: 203-229
- Rune Damgaard
- Paul Elliott
- Malte Gersch
- Christina Gladkova
- Martin Michel
- Jonathan Pruneda
- Alexander Schubert
- Yuri Shibata
- Joanne Usher