SUMO protein

Small Ubiquitin-like Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. SUMOylation is a post-translational modification involved in various cellular processes, such as nuclear-cytosolic transport, transcriptional regulation, apoptosis, protein stability, response to stress, and progression through the cell cycle [ [http://www.molecule.org/content/article/abstract?uid=PIIS1097276505011822 Molecular Cell - Hay ] ] .

SUMO proteins are similar to ubiquitin, and SUMOylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. Mature SUMO is produced when the last four amino acids of the C-terminus have been cleaved off to allow for formation of an isopeptide bond between the C-terminal glycine residue of SUMO and an acceptor lysine on the target protein.

SUMO family members often have dissimilar names; the SUMO homologue in yeast, for example, is called SMT3 (suppressor of mif two 3). Several pseudogenes have been reported for this gene.

Function

SUMO modification of proteins has many functions. Among the most frequent and best studied are protein stability, nuclear-cytosolic transport, and transcriptional regulation. Typically, only a small fraction of a given protein is SUMOylated and this modification is rapidly reversed by the action of deSUMOylating enzymes. SUMOylation of target proteins has been shown to cause a number of different outcomes including altered localisation and binding partners. The SUMO-1 modification of RanGAP1 (the first identified SUMO substrate) leads to its trafficking from cytosol to nuclear pore complex [ [http://www.ncbi.nlm.nih.gov/pubmed/8978815 A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and ... [J Cell Biol. 1996 - PubMed Result ] ] [ [http://www.ncbi.nlm.nih.gov/pubmed/9019411 A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2 [Cell 1997 - PubMed Result ] ] . The SUMO modification of hNinein leads to its movement from the centrosome to the nucleus [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16154161 SUMO-1 modification of centrosomal protein hNinein... [Life Sci. 2006 - PubMed Result ] ] . In many cases SUMO modification of transcriptional regulators correlates with inhibition of transcription [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16095902 [Curr Opin Genet Dev. 2005 - PubMed Result ] ] . Refer to the GeneRIFs of the SUMO proteins, e.g. human SUMO-1 [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=7341 Gene Result ] ] , to find out more.

There are 3 confirmed SUMO isoforms in humans; SUMO-1, SUMO-2 and SUMO-3. SUMO-2/3 show high a high degree of similarity to each other and are distinct from SUMO-1. SUMO-4 shows similarity to -2/3 but it is as yet unclear whether it is a pseudogene or merely restricted in its expression pattern. During mitosis, SUMO-2/3 localize to centromeres and condensed chromosomes, whereas SUMO-1 localizes to the mitotic spindle and spindle midzone, indicating that SUMO paralogs regulate distinct mitotic processes in mammalian cells [ [http://www.ncbi.nlm.nih.gov/pubmed/18374647 SUMO-2/3 modification and binding regulate the association of CENP-E with kinetochores and progression through mitosis [Mol Cell 2008 - PubMed Result ] ] . One of the major SUMO conjugation products associated with mitotic chromosomes arose from SUMO-2/3 conjugation of topoisomerase II, which is modified exclusively by SUMO-2/3 during mitosis [ [http://www.ncbi.nlm.nih.gov/pubmed/14597774 SUMO-2/3 regulates topoisomerase II in mitosis [ J Cell Biol. 2003 - PubMed Result ] ] . SUMO-2/3 modifications seem to be involved specifically in the stress response [ [http://www.ncbi.nlm.nih.gov/pubmed/10692421 Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3 [J Biol Chem. 2000 - PubMed Result ] ] . SUMO-1 and SUMO-2/3 can form mixed chains, however, because SUMO-1 does not contain the internal SUMO consensus sites found in SUMO-2/3, it is thought to terminate these poly-SUMO chains [ [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=AbstractPlus&list_uids=17938407 In vivo identification of human small ubiquitin-li... [Mol Cell Proteomics. 2008 - PubMed Result ] ] .Serine 2 of SUMO-1 is phosphorylated, raising the concept of a 'modified modifier' [ [http://www.ncbi.nlm.nih.gov/pubmed/18707152?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Phosphorylation of SUMO-1 Occurs in Vivo and Is Conserved through Evolution. [J Proteome Res. 2008 Aug 16; - PubMed Result ] ] .

Structure

SUMO proteins are small; most are around 100 amino acids in length and 12 kDa in mass. The exact length and mass varies between SUMO family members and depends on which organism the protein comes from. Although SUMO has very little homology with Ubiquitin at the amino acid level, it has a nearly identical structural fold.

The structure of human SUMO1 is depicted on the right. It shows SUMO1 as a globular protein with both ends of the amino acid chain (shown in red and blue) sticking out of the protein's centre. The spherical core consists of an alpha helix and a beta sheet. The diagrams shown are based on an NMR analysis of the protein in solution.

Prediction of SUMO attachment

Most SUMO-modified proteins contain the tetrapeptide consensus motif Ψ-K-x-D/E where Ψ is a hydrophobic residue, K is the lysine conjugated to SUMO, x is any amino acid (aa), D or E is an acidic residue. Substrate specificity appears to be derived directly from Ubc9 and the respective substrate motif. SUMOplot is an online free access software developed to predict the probability for the SUMO consensus sequence (SUMO-CS) to be engaged in SUMO attachment. [Gramatikoff K. et al. In Frontiers of Biotechnology and Pharmaceuticals, Science Press (2004) 4: pp.181-210.] The SUMOplot score system is based on two criteria: 1) direct amino acid match to the SUMO-CS observed and shown to bind Ubc9, and 2) substitution of the consensus amino acid residues with amino acid residues exhibiting similar hydrophobicity. SUMOplot has been used in the past to predict Ubc9 dependent sites. Seventeen (17) articles have been published so far for the complete list [http://www.abgent.com/doc/sumoplot click here] . [ [http://www.abgent.com/doc/sumoplot SUMOplot usage - list of 17 articles] ] Alternative prediction engines such as SUMOsp are also available [bioinformatics.lcd-ustc.org/sumosp/ ] .

SUMO Conjugation

SUMO conjugation to its target is analogous to that of Ubiquitin (as it is for the other Ubiquitin-like proteins such as NEDD 8). A C-terminal peptide is cleaved from SUMO by a protease (in human these are the SENP proteases or Ulp1 in yeast) using ATP to reveal a di-glycine motif. SUMO then becomes bound to an E1 enzyme (SUMO Activating Enzyme (SAE)) which is a heterodimer. It is then passed to an E2 which is a conjugating enzyme (Ubc9). Finally, one of a small number of E3 ligating proteins attaches it to the protein. In yeast, there are four SUMO E3 proteins, Cst9 [ [http://www.genesdev.org/cgi/content/full/20/15/2067 SUMO modifications control assembly of synaptonemal complex and polycomplex in meiosis of Saccharomyces cerevisiae - Cheng et al. 20 (15): 2067 - Genes and Development ] ] , Mms21, Siz1 and Siz2. While in ubiquitination an E3 is essential to add ubiquitin to its target, evidence suggests that the E2 is sufficient in Sumoylation as long as the consensus sequence is present. It is thought that the E3 ligase promotes the efficiency of sumoylation and in some cases has been shown to direct SUMO conjugation onto non-consensus motifs. E3 enzymes can be largely classed into PIAS proteins, such as Mms21 (a member of the Smc5/6 complex) and Pias-gamma and HECT proteins. Some E3's such as RanBP2 however are neither [ [http://www.nature.com/nsmb/journal/v11/n10/abs/nsmb834.html;jsessionid=AD17A0BE7A40B2E08091663D0C2BC720 The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type - Nature Structural & Molecular Biology ] ] . Recent evidence has shown that PIAS-gamma is required for the sumoylation of the transcription factor yy1 but it is independent of the zinc-RING finger (identified as the functional domain of the E3 ligases). SUMOylation is reversible and is removed from targets by specific SUMO proteases in an ATP dependent manner. In budding yeast, the Ulp1 SUMO protease is found bound at the nuclear pore, whereas Ulp2 is nucleoplasmic. The distinct subnuclear localisation of deSUMOylating enzymes is conserved in higher eukaryotes [ [http://www.ncbi.nlm.nih.gov/pubmed/17499995?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Modification in reverse: the SUMO proteases. [Trends Biochem Sci. 2007 - PubMed Result ] ]

References

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External links

* [http://www.whatissumo.com/ www.whatissumo.com] -Learn how to use SUMO as a protein expression and purification tag to increase quality and quantity of proteins
* [http://www.bostonbiochem.com/overview.php?prod=sumo Boston Biochem overview of SUMO reagents and the SUMOylation Cycle]
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=homologene&dopt=HomoloGene&list_uids=2514 SUMO1 homology group from HomoloGene]
* human SUMO proteins on ExPASy: [http://www.expasy.org/uniprot/P63165 SUMO1] [http://www.expasy.org/uniprot/P61956 SUMO2] [http://www.expasy.org/uniprot/P55854 SUMO3] [http://www.expasy.org/uniprot/Q6EEV6 SUMO4]
* [http://www.ebi.uniprot.org/uniprot-srv/uniProtView.do?proteinAc=Q5I0H3&pager.offset=0 UniProt entry for rat Sumo1]
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16125934 connection between ubiquitin & SUMO modification, 2005]
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16095902 effect of SUMO on transcription, 2005]
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15806321 possible link between Sumo & diabetes, 2005]
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12612601 Role of sumoylation in transcription, 2003]
* [http://www.stanford.edu/~mudgett/research.html Mary Beth Mudgett's lab (plants & bacterial infection)]
* [http://ohare.mcri.ac.uk/research.html Peter O'Hare's lab (Herpes virus)]
* [http://dir2.nichd.nih.gov/nichd/lgrd/sccr/sumo1_protein.htm Mary Dasso's section on cell cylce control]
* [http://faculty.jhsph.edu/default.cfm?faculty_id=455 Michael Matunis' lab]
* [http://www.jax.org/staff/mary_ann_handel.html Mary Ann Handel's lab (meiosis, spermatogenesis)]
* [http://www.rockefeller.edu/labheads/chua/ulp.php Nam-Hai Chua's lab (plants, protein modification)]
* [http://www.gzmb.uni-goettingen.de/faculty/f_melchior.html Frauke Melchior's personal page]
* [http://www.biochem.mpg.de/jentsch/ Stefan Jentsch's lab]
* [http://boneslab.bio.ntnu.no/AhusGeneral_info.html Bones lab (plant immunology) has a summary page on sumoylation]
* [http://www.abgent.com/doc/sumoplot Abgent's SUMOplot tool] - predicts sumoylation for a given protein