Tatham MH, Plechanovova A, Jaffray EG, Salmen H, Hay RT

The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the coordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond ...

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between the C-terminal carboxyl group of ubiquitin and the ε-amino group of a target lysine. However, ubiquitin is also known to conjugate to the sulphydryl of cysteine side chains and the α-amino group of protein N-termini, although the enzymes responsible for discrimination between different chemical groups have not been defined. Here we show that Ube2W (Ubc16) is an E2 ubiquitin conjugating enzyme with specific protein amino terminal monoubiquitylation activity. Ube2W not only conjugates ubiquitin to its own amino-terminus, but also to that of the small ubiquitin-like modifier SUMO in a manner dependent upon the SUMO targeted ubiquitin ligase RNF4. Furthermore, N-terminal monoubiquitylation of SUMO-2 primes it for further polyubiquitylation by the Ubc13/UEV1 E2 heterodimer, showing that N-terminal ubiquitylation regulate protein fate. This is the first description of an E2 conjugating enzyme with N-terminal ubiquitylation activity, and highlights the importance of E2 enzymes in the ultimate outcome of E3 mediated ubiquitylation.

Date: Apr. 08, 2013

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