Key Points
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SUMO (small ubiquitin-related modifier) proteins are ∼10-kD polypeptides that function as reversible post-translational protein modifiers. They form isopeptide bonds with ɛ-amino groups of acceptor Lys residues in hundreds of target proteins in a process termed sumoylation.
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Sumoylation requires a cascade of enzymatic steps that involves an E1 activating enzyme, an E2 conjugating enzyme and, in most cases, an E3 SUMO ligase. Owing to SUMO-specific isopeptidases, this modification is highly dynamic.
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Acceptor Lys residues in target proteins are frequently found in the consensus motif ΨKxE (in which Ψ is a branched aliphatic amino acid and x is any amino acid), although the number of targets with non-consensus acceptor sites is steadily increasing.
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Sumoylation alters the molecular interactions of modified target proteins by masking or adding interaction surfaces. Downstream consequences, which are target dependent, include changes in localization, activity and protein stability.
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A short non-covalent SUMO-interaction/binding motif (SIM/SBM) has been identified in selected SUMO enzymes, targets and downstream effectors. This motif contributes to the mechanism and consequences of sumoylation.
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Reversible sumoylation contributes to many distinct pathways, such as chromatin structure, DNA repair, transcription, cell-cycle progression and trafficking. Targets can be found in the nucleus, the cytoplasm, the plasma membrane and organelles such as the endoplasmic reticulum and mitochondria.
Abstract
A decade has passed since SUMO (small ubiquitin-related modifier) was discovered to be a reversible post-translational protein modifier. During this time many enzymes that participate in regulated SUMO-conjugation and -deconjugation pathways have been identified and characterized. In parallel, the search for SUMO substrates has produced a long list of targets, which appear to be involved in most cellular functions. Sumoylation is a highly dynamic process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified protein. At first glance, these effects have nothing in common; however, it seems that they all result from changes in the molecular interactions of the sumoylated proteins.
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Acknowledgements
We would like to thank all laboratory members for very enjoyable discussions and helpful comments. We are especially grateful for suggestions by the anonymous reviewers. The authors would like to acknowledge support by the EU network Rubicon and by the Deutsche Forschungsgemeinschaft (DFG). Finally, we apologize for all the important papers that could not be cited due to space limitations.
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Supplementary information S1 (table)
Saccharomyces cerevisiae proteins of the SUMO pathway (PDF 167 kb)
Supplementary information S2 (table)
Human proteins of the SUMO pathway (PDF 217 kb)
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Glossary
- SUMO-interaction/binding motif
-
A short motif in proteins that mediates non-covalent interaction with SUMO. This motif is characterized as hxhh or hhxh (in which h is Val, Ile or Leu and x is any amino acid), flanked by acidic amino acids, and in some cases by Ser residues.
- E1 activating enzyme
-
An enzyme that forms a high-energy bond (thioester) with the C-terminal Gly residue of ubiquitin or a ubiquitin-like protein in an ATP-dependent reaction.
- E2 conjugating enzyme
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An enzyme that accepts ubiquitin or a ubiquitin-like protein from an E1 enzyme and transfers it to a substrate protein via the formation of an isopeptide bond. This step usually requires cooperation with an E3 ligase.
- E3 ligase
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An enzyme that facilitates the transfer of ubiquitin or ubiquitin-like protein from an E2 enzyme to a substrate protein. Ubiquitin HECT E3 ligases form thioester intermediates with ubiquitin, whereas all other known E3 ligases form complexes with the thioester-charged E2 and the target.
- SP-RING motif
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A RING-related sequence (Sx2Cx15CxHx2C/Sx17Cx2C (in which x is any amino acid)) that is predicted to have a RING-like structure.
- RING domain
-
A sequence of Cys and His residues that binds two zinc cations: Cx2Cx(9–39)Cx(1–3)Hx(2–3)C/Hx2C/x(4–48)Cx2C (in which x is any amino acid).
- PIAS family
-
A group of SUMO E3 ligases, initially identified for their ability to repress the transcription factor STAT3 (PIAS: protein inhibitors of activated STAT). All PIAS proteins share a SAP domain (which binds nucleic acids), an SPRING and a SUMO-interaction/binding motif.
- Polycomb group (PcG) proteins
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A family of proteins, originally described in Drosophila melanogaster, that maintains the stable and heritable repression of several genes, including the homeotic genes.
- Sentrin-specific proteases
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(SENPs). Mammalian Cys proteases related to Saccharomyces cerevisiae Ulp1 and Ulp2. Like their yeast counterparts, most SENPs are SUMO-specific isopeptidases and C-terminal hydrolases (SENP8 is an exception).
- Nuclear pore complex
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(NPC). A macromolecular protein complex that is embedded in the nuclear envelope. NPCs allow the exchange of ions, metabolites and macromolecules between the nucleus and the cytoplasm.
- SUMO-acceptor site
-
The Lys residue in a target to which SUMO is coupled. It is frequently found in the sequence motif ΨKxE (in which Ψ is a bulky aliphatic amino acid and x is any amino acid).
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Geiss-Friedlander, R., Melchior, F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8, 947–956 (2007). https://doi.org/10.1038/nrm2293
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DOI: https://doi.org/10.1038/nrm2293
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