David Komander

Specificity in the ubiquitin system
Personal group site

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.

Structural diversity of polyubiquitin. Five differently linked diubiquitin molecules have been crystallised, revealing distinct interfaces and structures, rationalising how proteins can distinguish between them. For details, see Kulathu and Komander, Nat Rev Mol Cell Biol (2012).

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.

Selected Papers

Group Members

  • Paul Elliott
  • Jonathan Pruneda
  • Kirby Swatek
  • Alexander Schubert
  • Martin Michel
  • Michal Simicek
  • Rune Damgaard
  • Malte Gersch
  • Christina Gladkova
  • Joanne Usher