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

Abstract

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.