SUMOylation is the addition of a 97-amino acid peptide to the primary amine group of target lysine residues in the substrate protein by an isopeptide bond, via a pathway analogous to ubiquitination. There are four SUMO genes in the mammalian genome, termed SUMO-1–4. SUMO-2 and SUMO-3 differ by only 3 amino acids and are collectively referred to as SUMO-2/3. SUMO-1 shares 50% homology with SUMO-2/3 [1
]. Although SUMO-4 mRNA expression has been reported, as yet no SUMO-4 protein has been detected raising doubts as to whether it is physiologically relevant [2
]. Excellent reviews are available that detail the SUMOylation pathway (e.g. [1
]). Briefly, nascent SUMO peptides are matured by cleavage of C-terminal residues by sentrin-specific proteases (SENPs). Mature SUMO is then activated by the E1 enzyme, a heterodimer of SAE1 and SAE2 in mammals, and passed to the active site cysteine of the SUMO-specific conjugating enzyme, Ubc9. Ubc9 corresponds to an E2 ubiquitin ligase but, whereas there are many ubiquitin E2s, Ubc9 is the only SUMO E2 and is required by all three SUMO paralogues. Although in some cases it appears Ubc9 alone is sufficient for SUMOylation, E3 enzymes such as PIAS3 probably increase the substrate specificity of this process. As well as maturing nascent SUMO, SENPs actively deSUMOylate conjugated target proteins. There are six SENP proteins (SENP1–3 and SENP5–7) in mammals, which exhibit selectivity between the SUMO paralogues and have distinct subcellular localisations [11
]. A schematic of SUMOylation is shown in .
Figure 1 The SUMO pathway. Schematic diagram representing the major proteins involved in SUMO conjugation/deconjugation. Mature SUMO is first activated by the E1 enzyme complex (SAE1/SAE2), before being loaded onto the E2 ligase, Ubc9. Ubc9 then directly binds (more ...)
SUMOylation often (but not always) occurs at a consensus ψK
xD/E site (where ψ is a large hydrophobic residue) that directly binds Ubc9 [5
]. A region of negative charge C-terminal to the consensus site can enhance SUMOylation and this can arise from phosphorylation of nearby residues, providing a potential mechanism for the regulation of SUMOylation by phosphorylation [6
]. Much of the work on SUMOylation relates to its nuclear roles, for example regulation of transcription factors and nuclear export (for reviews see [7
]) and in mice Ubc9 knockout is embryonic lethal owing to defects in nuclear integrity and chromosomal segregation [9
It is well established that phosphorylation and ubiquitination play essential roles in regulating spine structure and synaptic function [10
]. SUMOylation is known to have long-term effects on neuronal function via regulation of transcription and nuclear traffic [4•
]. More recently, however, as we discuss below, it has been shown that SUMOylation also has more rapid, extra-nuclear roles, including regulating neuronal function by influencing pathways that control synaptic structure and function.