Abstract
Ubiquitination is a versatile posttranslational modification that elicits signaling roles to impact on various cellular processes and disease states. The versatility is a result of the complexity of ubiquitin conjugates, ranging from a single ubiquitin monomer to polymers with different length and linkage types. Recent studies have revealed the abundant existence of branched ubiquitin chains in which one ubiquitin molecule is connected to two or more ubiquitin moieties in the same ubiquitin polymer. Compared to the homotypic ubiquitin chain, the branched chain is recognized or processed differently by readers and erasers of the ubiquitin system, respectively, resulting in a qualitative or quantitative alteration of the functional output. Furthermore, certain types of branched ubiquitination are induced by cellular stresses, implicating their important physiological role in stress adaption. In addition, the current chemical methodologies of solid phase peptide synthesis and expanding genetic code approach have been developed to synthesize different architectures of branched ubiquitin chains. The synthesized branched ubiquitin chains have shown their significance in understanding the topologies and binding partners of the branched chains. Here, we discuss the recent progresses on the detection, functional characterization and synthesis of branched ubiquitin chains as well as the future perspectives of this emerging field.
Highlights
Protein ubiquitination, which is mediated by the consecutive action of E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme and E3 ubiquitin ligase, is one of the most elaborate and versatile posttranslational modifications
Besides the technology advances in detecting branched ubiquitination, the various tools for the in vitro synthesis of branched ubiquitin oligomers provide structural insights into the dynamic of branched chains and open up avenues for understanding the biochemical properties of various DUBs against ubiquitin conjugates branched at specific positions
With the technology advances in the detection of branched ubiquitination, the biological functions of several branched ubiquitin chain types have been unearthed in vivo [8,13]
Summary
Protein ubiquitination, which is mediated by the consecutive action of E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme and E3 ubiquitin ligase, is one of the most elaborate and versatile posttranslational modifications. All building blocks of the chain are connected through the same Lys or Met 1 residue and a total of eight different chain types can be formed Proteomics analyses demonstrated their coexistence in all cell types analyzed, albeit with different. Molecules 2020, 25, 5200 types can be formed Proteomics analyses demonstrated their coexistence in all cell types analyzed, albeit with different abundance [3,4,5]. These structurally distinct ubiquitin chains are recognized by abundance [3,4,5]. Since generation of branched ubiquitin chains in vivo often involves complicated processes with the coordinated action of different E2 or E3 enzymes, we will discuss the methods of synthesizing branched ubiquitin chains by chemical or chemical biology approaches
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