Journal Article

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

Gareau, Jaclyn R., Lima, Christopher D.

2010

Overview

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. Conjugation of the ubiquitin-like protein SUMO to proteins regulates many biological processes. Insights are emerging into mechanisms that regulate the SUMO modification pathway, including other post-translational modifications. Many substrates also harbour additional characteristics that facilitate their modification. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/200 / 631/80/458/1733 / 631/80/458/538 / 631/80/86 / Amino Acid Sequence / Animals / Binding proteins / Biochemistry / Biomedical and Life Sciences / Cancer Research / Cell Biology / Deoxyribonucleic acid / Developmental Biology / DNA / Enzymes / Humans / Life Sciences / Models, Biological / Models, Molecular / Phosphorylation / Physiological aspects / Post-translational modification / Protein Conformation / Protein Interaction Domains and Motifs - physiology / Proteins / review-article / Signal Transduction - physiology / Small Ubiquitin-Related Modifier Proteins - chemistry / Small Ubiquitin-Related Modifier Proteins - metabolism / Stem Cells / Substrate Specificity / Substrates / SUMO-1 Protein - chemistry / SUMO-1 Protein - metabolism / Sumoylation - physiology / Ubiquitin / Yeast