SUMO protein

Source: Wikipedia, the free encyclopedia.

In

transcriptional regulation, apoptosis, protein stability, response to stress, and progression through the cell cycle.[1]

SUMO proteins are similar to ubiquitin and are considered members of the ubiquitin-like protein family. 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 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 SUMO genes in the human genome.

Structure schematic of human SUMO1 protein made with iMol and based on PDB file 1A5R, an NMR structure; the backbone of the protein is represented as a ribbon, highlighting secondary structure; N-terminus in blue, C-terminus in red
The same structure, representing atoms as spheres, shows the shape of the protein; human SUMO1, PDB file 1A5R

Function

SUMO modification of proteins has many functions. Among the most frequent and best studied are protein stability,

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 localization and binding partners. The SUMO-1 modification of RanGAP1 (the first identified SUMO substrate) leads to its trafficking from cytosol to nuclear pore complex.[2][3] The SUMO modification of ninein leads to its movement from the centrosome to the nucleus.[4] In many cases, SUMO modification of transcriptional regulators correlates with inhibition of transcription.[5] One can refer to the GeneRIFs of the SUMO proteins, e.g. human SUMO-1,[6]
to find out more.

There are 4 confirmed SUMO

isoforms in humans; SUMO-1, SUMO-2, SUMO-3 and SUMO-4. At the amino acid level, SUMO1 is about 50% identical to SUMO2.[citation needed] SUMO-2/3 show a high degree of similarity to each other and are distinct from SUMO-1. SUMO-4 shows similarity to SUMO-2/3 but differs in having a Proline instead of Glutamine at position 90. As a result, SUMO-4 isn't processed and conjugated under normal conditions, but is used for modification of proteins under stress-conditions like starvation.[7] 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.[8] 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.[9] SUMO-2/3 modifications seem to be involved specifically in the stress response.[10] 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.[11]
Serine 2 of SUMO-1 is phosphorylated, raising the concept of a 'modified modifier'.[12]

DNA damage response

Cellular DNA is regularly exposed to DNA damaging agents. A DNA damage response (DDR) that is well regulated and intricate is usually employed to deal with the potential deleterious effects of the damage. When DNA damage occurs, SUMO protein has been shown to act as a molecular glue to facilitate the assembly of large protein complexes in repair foci.[13] Also, SUMOylation can alter a protein's biochemical activities and interactions. SUMOylation plays a role in the major DNA repair pathways of base excision repair, nucleotide excision repair, non-homologous end joining and homologous recombinational repair. [13] SUMOylation also facilitates error prone translation synthesis.

Structure

SUMO proteins are small; most are around 100

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 sequence identity with ubiquitin (less than 20%) at the amino acid level, it has a nearly identical structural fold. SUMO protein has a unique N-terminal extension of 10-25 amino acids which other ubiquitin-like proteins do not have. This N-terminal is found related to the formation of SUMO chains.[14]

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

NMR
analysis of the protein in solution.

Prediction of SUMO attachment

Most SUMO-modified proteins contain the tetrapeptide consensus

substrate
motif. Currently available prediction programs are:

SUMO attachment (SUMOylation)

SUMO attachment to its target is similar to that of ubiquitin (as it is for the other ubiquitin-like proteins such as NEDD 8). The SUMO precursor has some extra amino acids that need to be removed, therefore a C-terminal peptide is cleaved from the SUMO precursor by a protease (in human these are the SENP proteases or Ulp1 in yeast) to reveal a di-glycine motif. The obtained SUMO then becomes bound to an E1 enzyme (SUMO Activating Enzyme (SAE)) which is a heterodimer (subunits

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. On Chromosome 17 of the human genome, SUMO2 is near SUMO1+E1/E2 and SUMO2+E1/E2, among various others. Some E3's, such as RanBP2, however, are neither.[20] 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 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.[21]

DeSUMOylation

SUMO can be removed from its substrate, which is called deSUMOylation. Specific proteases mediate this procedure (SENP in human or Ulp1 and Ulp2 in yeast).[14]

Role in protein purification

Recombinant proteins expressed in E. coli may fail to fold properly, instead forming aggregates and precipitating as inclusion bodies.[22] This insolubility may be due to the presence of codons read inefficiently by E. coli, differences in eukaryotic and prokaryotic ribosomes, or lack of appropriate molecular chaperones for proper protein folding.[23] In order to purify such proteins it may be necessary to fuse the protein of interest with a solubility tag such as SUMO or MBP (maltose-binding protein) to increase the protein's solubility.[23] SUMO can later be cleaved from the protein of interest using a SUMO-specific protease such as Ulp1 peptidase.[23]

Human SUMO proteins

See also

References

  1. PMID 15808504
    .
  2. PMID 8978815
    .
  3. S2CID 17819277
    .
  4. PMID 16154161
    .
  5. PMID 16095902
    .
  6. ^ SUMO1 SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae)
  7. PMID 18708028
    .
  8. PMID 18374647
    .
  9. PMID 14597774
    .
  10. PMID 10692421
    .
  11. PMID 17938407
    .
  12. PMID 18707152
    .
  13. ^
    PMID 28115630
    .
  14. ^
    S2CID 30462190
    .
  15. ^ Gramatikoff K. et al. In Frontiers of Biotechnology and Pharmaceuticals, Science Press (2004) 4: pp.181-210.
  16. S2CID 14360760
    .
  17. S2CID 4900031
    .
  18. PMID 26142185
    .
  19. PMID 16847351
    .
  20. S2CID 28085778
    .
  21. PMID 17499995
    .
  22. PMID 19892177
    .
  23. ^
    ISBN 978-1-4939-1034-2
    .

Further reading

External links

Programs for prediction SUMOylation:

  • SUMOplot Analysis Program — predicts and scores SUMOylation sites in your protein (by Abgent)
  • seeSUMO - prediction of SUMOylation sites
  • SUMOsp - prediction of SUMOylation sites
  • JASSA - Predicts and scores SUMOylation sites and SIM (SUMO interacting motif)

Research laboratories

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