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The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition

Nature Reviews Molecular Cell Biology volume 11, pages 861–871 (2010)Cite this article

Subjects

Key Points

  • Post-translation modification of proteins by ubiquitin and ubiquitin-like proteins, such as small ubiquitin-related modifier (SUMO), requires the sequential activities of E1, E2 and E3 enzymes. SUMO modification regulates a wide array of cellular processes that include transcription, replication, chromosome segregation, DNA repair and response to environmental stress.

  • The SUMO pathway relies on a single E1 and E2 enzyme and just a few E3 enzymes to regulate substrate specificity. This is achieved in part because the SUMO E2 can specifically recognize and conjugate SUMO to substrates in the absence of an E3 by recognition of a ψKX(D/E) consensus motif in the substrate, where ψ is a large hydrophobic residue. Longer consensus motifs for SUMO interaction with the E2 also exist.

  • SUMO-interacting motifs (SIMs) mediate non-covalent interactions between SUMO and SIM-containing proteins. SIMs are characterized by a short stretch of hydrophobic amino acids that are often flanked by acidic residues. SIMs are present in SUMO enzymes, SUMO substrates and SUMO-binding proteins.

  • SUMO E3 ligases catalyse SUMO transfer through at least two distinct mechanisms. They can bind an E2∼SUMO thioester complex and hold it in a productive orientation for catalysis in complexes in which the E2 mediates substrate specificity, or they can interact directly with both the substrate and E2∼SUMO to facilitate SUMO transfer to the substrate Lys acceptor.

  • Phosphorylation of SUMO enzymes and SUMO substrates has been shown to contribute to the regulation of the SUMO pathway. Examples exist that illustrate both positive and negative regulation of SUMO modification by phosphorylation.

  • Substrate Lys residues that are modified by SUMO are sometimes sites for other post-translational modifications, such as ubiquitylation or acetylation. Switching between these various modifications can influence downstream signalling.

Abstract

Proteins of the small ubiquitin-related modifier (SUMO) family are conjugated to proteins to regulate such cellular processes as nuclear transport, transcription, chromosome segregation and DNA repair. Recently, numerous insights into regulatory mechanisms of the SUMO modification pathway have emerged. Although SUMO-conjugating enzymes can discriminate between SUMO targets, many substrates possess characteristics that facilitate their modification. Other post-translational modifications also regulate SUMO conjugation, suggesting that SUMO signalling is integrated with other signal transduction pathways. A better understanding of SUMO regulatory mechanisms will lead to improved approaches for analysing the function of SUMO and substrate conjugation in distinct cellular pathways.

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Figure 1: The SUMO conjugation cycle.
Figure 2: SUMO consensus motifs and SUMO-interacting motifs.
Figure 3: Roles of SUMO-interacting motifs.
Figure 4: Phosphorylation and SUMO modification regulate transcription factors.
Figure 5: Recruitment to PCNA by ubiquitin-like proteins.

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Acknowledgements

J.R.G. and C.D.L. were supported in part by US National Institutes of Health grant R01 GM065872.

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  1. Structural Biology Program, Sloan–Kettering Institute, 1275 York Avenue, New York, New York, USA

    Jaclyn R. Gareau & Christopher D. Lima

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Glossary

Ubiquitin

A protein with a β-grasp fold that can be conjugated post-translationally to proteins through an E1–E2–E3 enzyme cascade, most often to Lys residues within the substrate.

E1

An enzyme that activates ubiquitin and ubiquitin-like proteins (including SUMO) through sequential adenylation and thioester bond formation with their carboxyl termini.

E2

An enzyme that forms a thioester bond with ubiquitin (Ub) and ubiquitin-like (Ubl) proteins (including SUMO) following transfer from an E1 enzyme. E2 enzymes are referred to as Ub or Ubl-conjugating enzymes because they can conjugate the Ub or Ubl protein directly to a substrate. However, E2 enzymes often require E3 ligases for proper function.

E3

Often referred to as a protein ligase, an E3 enzyme either facilitates the transfer of ubiquitin or ubiquitin-like proteins (including SUMO) from the E2-conjugating enzyme to a substrate or catalyses thioester bond transfer between the E2 and E3 Cys before substrate conjugation, as is the case for HECT E3s.

Ulps and SENPs

(Ubiquitin-like protein-specific proteases and sentrin-specific proteases). A family of Cys proteases that process SUMO to its mature form and deconjugate SUMO from modified substrates.

RanBP2

(Ran-binding protein 2). A component of the nuclear pore complex that possesses SUMO E3 protein ligase activity. A domain within RanBP2 interacts directly with SUMO-modified Ran GTPase-activating protein 1 (RanGAP1) in a stable complex with ubiquitin-like conjugating enzyme 9.

SP-RING

A domain present in the Siz and PIAS family of SUMO E3s that is structurally similar to the RING domains of ubiquitin E3 ligases, which coordinate two zinc ions and interact with E2∼ubiquitin thioesters to facilitate ubiquitin transfer to a substrate. By contrast, SP-RING domains coordinate a single zinc ion and work in conjunction with the Siz/PIAS carboxy-terminal domain to activate the E2∼SUMO thioester during conjugation.

Siz/PIAS family

A family of SUMO E3 ligases that contain an SP-RING and Siz/PIAS carboxy-terminal domain that coordinate the E2∼SUMO thioester. These proteins also contain conserved SAP and PINIT domains that have been implicated in substrate specificity by directing protein–DNA or protein–protein interactions.

PDSM

A phosphorylation-dependent SUMO motif that is composed of an extended consensus motif, ψKX(D/E)XXSP, where S is the Ser that is phosphorylated. Phosphorylation of the Ser enhances E2 enzyme binding and modification of the Lys in the motif.

RanGAP1

(Ran GTPase-activating protein 1). A Ran GTPase-activating protein and the first SUMO substrate identified. The carboxy-terminal domain of RanGAP1 is both necessary and sufficient for modification by SUMO. This domain includes a SUMO consensus motif and additional elements that interact directly with the E2 enzyme.

PINIT domain

A domain in the Siz/PIAS E3 ligase family, named after a conserved five amino acid PINIT motif. The PINIT domain is located amino-terminal to the SP-RING and Siz/PIAS carboxy-terminal domain and is thought to be a substrate-binding domain.

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Gareau, J., Lima, C. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 11, 861–871 (2010). https://doi.org/10.1038/nrm3011

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