Diversity of degradation signals in the ubiquitin–proteasome system

Abstract

Substrate proteins that are destined for elimination are initially attached to polymers of the highly conserved ubiquitin protein. This covalent modification of the substrate targets it to a large protease complex, the 26S proteasome. The attachment of ubiquitin to substrates usually requires the action of three enzymes. E1 ubiquitin-activating enzyme activates the ubiquitin C terminus in an ATP-consuming reaction; E2 ubiquitin-conjugating enzyme receives the activated ubiquitin from E1 and transfers it to a substrate bound to a third enzyme, an E3 ubiquitin-protein ligase. A degradation signal, or 'degron', is generally defined as a minimal element within a protein that is sufficient for recognition and degradation by a proteolytic apparatus. Ubiquitin-pathway degrons require specific E3-binding determinants, an appropriate ubiquitin modification site and a proteasomal degradation initiation site, that allow substrate unfolding and translocation into the proteasome core to occur. The most common acceptor site for polyubiquitin chain addition is a Lys ε-amino group. For some proteins, only one or a few Lys residues can be efficiently ubiquitylated. This implies that for these substrates, the position of the ubiquitin acceptor site or the local structure surrounding it serves as a determinant for degron function. The N-terminal α-amino group and Cys, Ser or Thr residues might also be ubiquitylated in a context-specific manner. Degron activity is regulated in many ways. Post-translational modifications activate many degrons. Examples of such modifications are protein phosphorylation, hydroxylation and proteolytic cleavage. Alternatively, cryptic degrons might be revealed when a protein assumes a specific conformation or assembly state. Polypeptides that fail to assume their native tertiary or quaternary structures, collectively referred to as protein quality control substrates, are often subject to this latter mode of substrate recognition. Combined structural and functional studies of degrons are essential for a full understanding of how the ubiquitin–proteasome system is deployed in vivo.