Reading the ubiquitin code

• Ubiquitin codes:

  • Monoubiquitin - trafficking, endocytosis, gene expression, gene silencing
  • K63 - DNA damage tolerance, trafficking, translation, kinase activation
  • K48 - proteasome
  • K29 - proteasome
  • k6, k11 - unknown
• Polyubiquitin chains defer depending on the lysine linkage position causing different signals
• Ubiquitin receptors are involved in the signal transduction - reads the ubiquitin code
• Modification with ubiquitin allows new non covalent protein protein interactions
• K48 linkage - protein degradation

  • S5a subunit of 26S proteasome binds directly to the ubiquinated protein
  • S2 subunit binds indirectly via hHR23a
• K63 linkage - signal transduction

  • Receptor activation leads to the K63 linkage ubiquitination of protein
  • Polyubiquitin chain signals pathway activation by non covalent interaction
• Ubiquitin receptors recognise ubiquitin on polyubiquitin chains through their ubiquitin binding domain forming non covalent interactions
• Different ubiquitin binding domains can recognise:

  1. Hydrophobic surfaces (isoleucine 44)
  2. Acidic surfaces (aspartic acid 58)
  3. C terminal tail if free
  4. Others
• Higher affinity binding is achieved by having multiple ubiquitin binding domains on the same ubiquitin receptor - avidity
• Close confirmation of K48-linked polyubiquitin chains arise as two isoleucine 44 surfaces on neighbouring ubiquitins participate in a non-covalent hydrophobic interaction
• Some ubiquitin binding domains can recognise isopeptide linkages in polyubiquitin chains
• Many human diseases are caused by mutations affecting E3 enzymes