The UBE2E Proteins as Conjugating Dispersers: Extending Function with Extended Extensions

Abstract

In this issue of the Journal of Molecular Biology, Schumacher et al. investigate the molecular mechanisms underlying the ability of the members of Class II ubiquitin-conjugating enzymes (E2s) to catalyze the formation of polyubiquitin chains [1]. In addition to the highly conserved catalytic domain (the core ubiquitin-conjugating domain, UBC, of ~150 residues), the human UBE2E proteins studied here contain N-terminal intrinsically disordered (ID) extensions of different lengths [2]. The authors suggest that these extended extensions are a key for extending the E2 functionality. The impact of this important observation goes far beyond the understanding of how the ubiquitination machinery acts, since (a) it argues that studying the intact proteins, not just their core catalytic domains, is important for complete understanding of protein functionality, and (b) it provides new clues on how the protein functionality can be controlled and modulated via non-catalytic and therefore seemingly useless extended extensions, ID regions. A brief description of what is extended (i.e., a short description of the protein intrinsic disorder phenomenon with the focus on disordered tails) from what (i.e., an overview of the ubiquitination machinery with the focus on UBE2E proteins) is given below to help better appreciate the importance of these conclusions. The last decade and a half witnessed an increased recognition that a biologically active protein is not obligated to possess a unique three-dimensional structure as a whole or in part and that many biologically important functions may originate from the lack of ordered structure in a protein molecule [3– 6], and these functions are complementary to the functions of ordered proteins [3,7–9]. Such structureless functional proteins andprotein domainsare known