What are small ubiquitin-related modifiers (SUMOs)?

SUMOs (small ubiquitin-related modifiers) as their name suggests have a similar structure to the ubiquitin molecule, known as the ubiquitin-fold, and covalently modify their target proteins on lysine residues in a similar manner to ubiquitin. Yet ubiquitin and SUMOs show only 20% sequence homology. The N-termini of SUMOs also possess a 10-25 amino acid extension not seen in ubiquitin- the only function that has been assigned to this extension so far is the formation of SUMO chains.

Initially expressed in a pro-protein form SUMOs undergo cleavage of 2-11 amino acids from their C-terminus by SUMO proteases to enable their functionality, allowing their conjugation to target proteins. The consensus SUMO acceptor site was mapped after analysing the acceptor Lys residues in some of its target proteins. The acceptor sequence is ?KxE (where ? is an aliphatic branched aa and x is any aa). By comparison over 15 different ubiquitin acceptor sites have been identified so far1.
It appears that SUMOs are present throughout the eukaryotic kingdom. The genomes of yeast,C.elegans and D.melanogaster all encode a single SUMO, whilst plants may express up to eight different SUMOs. Four distinct SUMOs- SUMO1-SUMO4 have been identified in humans, with SUMO1-SUMO3 being expressed ubiquitously. SUMO4 is restricted to the kidney, lymph nodes and spleen. SUMO2 and SUMO3 share 97% sequence homology, yet they each share only 50% homology with SUMO1. This is reflected at the functional level where research shows that in vivo SUMO1 and SUMO2/3 serve separate functions being conjugated to different targets. However SUMO4 remains a mystery, as it’s still unclear whether this isoform can be processed to the mature conjugate-competent form1.
SUMOylation is an essential process in most organisms, including S.Cerevisiae, C.elegans, A.thalianaand mice, though we still don’t know whether individual SUMOs are essential in organisms that have multiple proteins. However, disruption of SUMO1 in mice resulted in embryonic lethality and SUMO haploinsufficiency gave rise to a developmental defect of a split lip and palate in mice and possibly in humans2.
Hundreds of SUMO target proteins have been identified with seemingly unrelated intracellular functions, including the nuclear import of RanGAP1, control of subcellular architecture by SUMOylation of PML and SP100 to retain nuclear body structure and the spatial control of transcription factor activity, such as the sequestration of Daxx within PML-nuclear bodies to remove transcriptional repression1,3. These findings led to the initial assumption that whilst ubiquitin functioned to target proteins for degradation via the proteasome, SUMOylation served to regulate intracellular protein activity and function.
But in cell regulation, a multitude of tricks has to be achieved with a limited set of playing cards, so the cell makes use of combinations of post-translational modifications to increase its ability to respond dynamically to different circumstances. Increasing knowledge of the roles of SUMOylation and ubiquitination has blurred the lines between the clean-cut classical roles of each of these post-translational modifications.
Cross-talk between the ubiquitin and SUMO pathways has been identified and found to function in three major ways: (i) cooperatively and sequentially, typically with SUMOylation preceding ubiquitination, as in the case of SUMOylation of PML following arsenic treatment for acute promyelocytic leukemia, SUMOylation allows RFN4 to recognise the PML molecule leading to its polyubiquitination and targeting to the proteasome; (ii) antagonisitically on the same residue, for example the de-ubiquitinating enzyme USP25m in muscle, where ubiquitination of Lys99 rescues ubiquitin labelled MyBPC1 from proteasomal degradation, whereas SUMOylation of Lys99 impairs its de-ubiquitinating function, resulting in the degradation of MyBPC1; (iii) differentially, as for modification of Lys164 in PCNA following DNA damage, where SUMOylation results in the prevention of homologous recombination, whilst ubiquitination results in DNA repair4.
So it seems that whether unravelling individual isoform function or unpicking cellular SUMO and ubiquitin cross-talk, there is still a way to go to understanding SUMO function.
As we announced last week, our new online catalogue of Affimer products has a wide range of affinity reagents for life scientists to draw upon. Amongst these are a number of SUMO isoforms in different organisms to help you break down the mechanisms at play in these pathways. Our range of SUMO products can be found in our catalogue