The Ubiquitin Enigma: Progress in the Detection and Chemical Synthesis of Branched Ubiquitin Chains

Abstract

Ubiquitin chains with distinct topologies play essential roles in eukaryotic cells. Recently, it was discovered that multiple ubiquitin units can be ligated to more than one lysine residue in the same ubiquitin to form diverse branched ubiquitin chains. Although there is increasing evidence implicating these branched chains in a plethora of biological functions, few mechanistic details have been elucidated. This concept article introduces the function, detection and chemical synthesis of branched ubiquitin chains; and offers some future perspective for this exciting new field.

A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes

“…Branched Ub polymers are emerging cellular signals and have been shown to play important roles in endocytosis of host proteins by viruses (K11/K63-branched chains) 3 and by enhancing proteasomal degradation of cell cycle proteins (K11/K48-branched chains) 9 . Strategies to generate branched chains rely hitherto on the combination of different linkage-specific E2-enzymes with mutant Ubs and DUBs 17 , sophisticated chemical protein synthesis protocols 13 , 45 , 46 , or on using click chemistry to produce non-natively triazole-linked branched chains 14 . Furthermore, approaches based on thiol-ene coupling in combination with cysteine-mutants 15 , 47 and silver-catalyzed chemical condensation together with genetic code expansion 48 have been used to build simple branched triUbs.…”