Key Points
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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.
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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.
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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.
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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.
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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.
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Combined structural and functional studies of degrons are essential for a full understanding of how the ubiquitin–proteasome system is deployed in vivo.
Abstract
The ubiquitin–proteasome system degrades an enormous variety of proteins that contain specific degradation signals, or 'degrons'. Besides the degradation of regulatory proteins, almost every protein suffers from sporadic biosynthetic errors or misfolding. Such aberrant proteins can be recognized and rapidly degraded by cells. Structural and functional data on a handful of degrons allow several generalizations regarding their mechanism of action. We focus on different strategies of degron recognition by the ubiquitin system, and contrast regulatory degrons that are subject to signalling-dependent modification with those that are controlled by protein folding or assembly, as frequently occurs during protein quality control.
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Acknowledgements
We thank J. Bloom, Y. Reiss and Y. Xie for comments on the manuscript. Work from the laboratory of M.H. was supported by grants from the National Institutes of Health, USA (GM046904, GM053756 and GM083050). Work in the laboratory of T.R. is supported by the European Union (grant IRG-205425) and by the Lejwa Fund for Biochemistry.
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DATABASES
FURTHER INFORMATION
Glossary
- RING domain
-
'Really interesting new gene' motif that consists of a defined pattern of Cys and His residues that coordinate two zinc ions. This motif is engaged in ubiquitin ligation through the recruitment and positioning of the E2 enzyme.
- UBR box
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A ∼70-residue zinc-finger-like motif in E3 ubiquitin ligases that serves as a substrate recognition domain for N-end rule substrates.
- F-box domain
-
A protein motif of ∼50 residues that functions as a binding site for the S-phase-kinase-associated protein-1 (SKP1) adaptor protein. F-box proteins contain additional protein–protein interaction motifs, such as WD40 or leucine-rich repeats, and are the substrate recognition subunits of SCF ligases.
- WD40 repeat
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A repeat sequence of 40 amino acids with a characteristic Trp-Asp motif that was first found in the β-subunit of heterotrimeric G proteins and is involved in protein–protein interactions. F-box motif-containing proteins often also have these repeats.
- Tetratricopeptide repeat (TPR) motif
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Tandem repeats of a degenerate 34-amino-acid sequence that mediate protein–protein interactions.
- HECT domain
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(Homologous to E6-AP C terminus domain). HECT- and RING-domain-containing proteins are the two main classes of E3 ubiquitin ligases. In contrast to RING ligases, HECT-domain ligases form an essential thioester intermediate with ubiquitin as it is being transferred from the E2 enzyme to the substrate.
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Ravid, T., Hochstrasser, M. Diversity of degradation signals in the ubiquitin–proteasome system. Nat Rev Mol Cell Biol 9, 679–689 (2008). https://doi.org/10.1038/nrm2468
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DOI: https://doi.org/10.1038/nrm2468
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