Key Points
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The reversible attachment of ubiquitin chains regulates the activity, localization and/or stability of a myriad of cellular proteins.
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The formation of ubiquitin chains requires the sequential action of three types of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s).
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Humans express at least 38 E2 genes. E2s contain a highly conserved catalytic ubiquitin-conjugating (UBC) domain that interacts with E1s and E3s. Several E2s possess amino- or carboxy-terminal appendices that modulate their interaction with E3s or enable their association with E2 cofactors.
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E2s are key regulators of ubiquitin chain assembly, and E2s with specific roles in ubiquitin chain initiation or elongation have been described. Some E2s catalyse both initiation and elongation with high specificity and efficiency.
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E2s can determine the processivity of ubiquitin chain formation. They have evolved distinct strategies to increase the processivity of chain formation, including the recognition of substrate motifs or the preassembly of ubiquitin chains on their active sites.
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E2s are crucial regulators of ubiquitin chain topology. Most linkage-specific E2s bind to the acceptor ubiquitin in a non-covalent manner to orient a particular Lys residue relative to the E2 active site (charged with the donor ubiquitin).
Abstract
The modification of proteins with ubiquitin chains can change their localization, activity and/or stability. Although ubiquitylation requires the concerted action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s), it is the E2s that have recently emerged as key mediators of chain assembly. These enzymes are able to govern the switch from ubiquitin chain initiation to elongation, regulate the processivity of chain formation and establish the topology of assembled chains, thereby determining the consequences of ubiquitylation for the modified proteins.
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Acknowledgements
We thank the members of our laboratories for many stimulating discussions. We are grateful to J. Schaletzky for discussions and critically reading the manuscript and C. Wolberger (Johns Hopkins University, Maryland, USA) for providing the coordinates of the Mms2-bound ubiquitin. The work in our laboratories is funded by a National Institutes of Health Director's New Innovator Award (M.R.), RO1 5R01GM083064-02 (M.R.), a March of Dimes grant (M.R.), and the intramural research programme of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH (Y.Y.). M.R. is a Pew Scholar.
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Supplementary information S1 (table) | A comprehensive list of the known human E2 enzymes and their key features. (PDF 246 kb)
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Glossary
- Ubiquitin-interacting motif
-
A small motif that mediates the interaction of a protein with the hydrophobic patch of ubiquitin around Ile44.
- Ubiquitin-associated (UBA) domain
-
A protein domain that forms a three-helix bundle and interacts with hydrophobic regions of ubiquitin.
- 26S proteasome
-
A multisubunit protease that degrades proteins with attached ubiquitin chains. It contains a barrel-like 20S proteolytic core particle that houses the active sites and a 19S regulatory particle that governs substrate recognition and entry into the 20S core particle.
- HECT domain
-
A domain of ∼40 kDa (350 amino acids) that is found at the C terminus of HECT E3s. It contains a catalytic Cys residue that accepts ubiquitin from an E2 to form a ubiquitin thioester intermediate before transferring the ubiquitin to substrates.
- RING domain
-
A domain that is present in most E3s and is defined by the consensus sequence CX2CX(9–39)CX(1–3)HX(2–3)C/HX2CX(4–48)CX2C (where X means any amino acid). It coordinates two structural zinc cations.
- Ubiquitin-conjugating (UBC) domain
-
A conserved core domain of ∼150 residues that is found in all E2s, including those for UBLs. It contains the catalytic Cys residue of E2s.
- 310-helix
-
A type of secondary protein structure in which the amino acids are in a right-handed helical arrangement. The hydrogen bonds are formed between the NH group of an amino acid and the CO group of the amino acid three residues earlier (as opposed to four residues earlier in an α-helix).
- Ubiquitin fold domain
-
A domain found in E1s that mediates binding to an E2 and forms a similar structure to ubiquitin.
- TEK box
-
A Lys-rich region in APC/C substrates downstream of initial APC/C recognition sites (such as the D box or KEN box), which promotes initiation of ubiquitin chain formation.
- D box
-
The amino acid sequence RXXL(X)nN (where X means any amino acid), which mediates binding of an APC/C substrate to the co-activators Cdc20 and Cdh1 and potentially also to subunits of the core APC/C.
- KEN box
-
The amino acid sequence KEN(X)nP (where X means any amino acid), which mediates binding of APC/C substrates to the co-activator Cdh1.
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Ye, Y., Rape, M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 10, 755–764 (2009). https://doi.org/10.1038/nrm2780
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DOI: https://doi.org/10.1038/nrm2780
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