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Small Ubiquitin-related 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.
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.
SUMO family members often have dissimilar names; the SUMO1 homologue in yeast, for example, is called SMT3 (suppressor of mif two 3). Several pseudogenes have been reported for this gene.
Additional recommended knowledge
SUMO modification of proteins has many functions. Among the most frequent and best studied are protein stability, nuclear-cytosolic transport, transcriptional regulation (mostly transcriptional repression). As opposed to ubiquitin modification which targets proteins for degradation, SUMOylation increases a protein's lifetime. It can also change a protein's location in the cell. For example, the Sumo modification of hNinein leads to its movement from the centrosome to the nucleus . In most cases Sumo attachment to transcriptional regulators correlates with inhibition of transcription . There are many more proposed functions. Refer to the GeneRIFs of the Sumo proteins, e.g. human SUMO1 , to find out more.
SUMO-1 is the main SUMO in human cells and is the one that organisms like yeast show the most similarity to. However, there are a further 3 isoforms in humans. SUMO-2/3 show high similarity to each other more so then to SUMO-1. On stress the free SUMO-2/3 pool disappears and a range of specific SUMO-2/3 modifications occur. They seem to be involved specifically in the stress response. SUMO-4 shows similarity to -2/3. Until recently it was thought SUMO-4 was either tissue specific (pancreas) or a pseudo gene. Evidence is now indicating it is the former and SUMO-4 defects may be involved in Type-1 and -2 diabetes.
SUMO-1 and SUMO-2/3 form mixed chains .
Sumo proteins are small proteins; 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. For example, human SUMO1, also shown in the figures, is 101 residues long and has a mass of 11.6 kDa. Its homologues in rat and mice are also 101 residues long, while the presumed relative in C. elegans has only 91 amino acids.
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 motif B-K-x-D/E where B 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. 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 extensively used in the past to predict Ubc9 dependent sites. Seventeen (17) articles have been published so far for the complete list click here.
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 two SUMO E3 proteins, Siz1 and Siz2. Whilst in ubiquitination an E3 is essential to add ubiquitin to its target evidence suggests that the conjugator is sufficient in Sumoylation as long as the consensus sequence is present. It is thought that the E3 ligase aids enhancement of Sumoylation and facilitates attachment when this consensus sequence is absent. The B-K-x-D/E motif is not an absolut requirement for SUMO binding. E3 ligases are more abundant than E1 and E2 for SUMO. The most common are the PIAS proteins of which Nse2 (Mms21) a member of the Smc5/6 complex and Pias-gamma are the most well known. There are also the HECT proteins and E3's are known to arise from a complex of proteins such as with RanGap. 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). It is as yet unknown whether there is another dimension to SUMO conjugation or if this is specific to yy1. Sumoylation is reversible and is removed from targets by a protease in an ATP dependant manner. The Ulp2 protease is found bound at the nuclear pore and maybe very important in regulating the localisation of proteins to the nucleous; a known role of SUMO. SUMO has also been shown to form chains. It is thought that these preassemble on the conjugator and are then passed to the target. The biological significance of these is yet unknown.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "SUMO_protein". A list of authors is available in Wikipedia.|