SUMO protein

From Wikipedia, the free encyclopedia

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.[1]

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 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.

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 represented with atoms represented as spheres to show 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, 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 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 hNinein 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 SUMO4. 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-2/3 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]

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 sequence identity 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. Currently available prediction programs are:

  • SUMOplot - online free access software developed to predict the probability for the SUMO consensus sequence (SUMO-CS) to be engaged in SUMO attachment.[13] 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.
  • seeSUMO - uses random forests and support vector machines trained on the data collected from the literature[14]
  • SUMOsp - uses PSSM to score potential sumoylation peptide stites. It can predict sites followed the ψKXE motif and unusual sumoylation sites contained other non-canonical motifs.[15]

SUMO Attachment

SUMO attachment to its target is similar 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) 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,[16] 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.[17] 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.[18]

See also

References

  1. ↑ Hay RT (Apr 2005). "SUMO: a history of modification". Mol. Cell 18 (1): 1–12. doi:10.1016/j.molcel.2005.03.012. PMID 15808504. 
  2. ↑ Matunis MJ, Coutavas E, Blobel G (Dec 1996). "A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex". J Cell Biol. 135 (6 Pt 1): 1457–70. doi:10.1083/jcb.135.6.1457. PMC 2133973. PMID 8978815. 
  3. ↑ Mahajan R, Delphin C, Guan T, Gerace L, Melchior F (Jan 1997). "A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2". Cell 88 (1): 97–107. doi:10.1016/S0092-8674(00)81862-0. PMID 9019411. 
  4. ↑ Cheng TS, Chang LK, Howng SL, Lu PJ, Lee CI, Hong YR (Feb 2006). "SUMO-1 modification of centrosomal protein hNinein promotes hNinein nuclear localization". Life Sci. 78 (10): 1114–20. doi:10.1016/j.lfs.2005.06.021. PMID 16154161. 
  5. ↑ Gill G (Oct 2005). "Something about SUMO inhibits transcription". Current Opinion in Genetics & Development 15 (5): 536–41. doi:10.1016/j.gde.2005.07.004. PMID 16095902. 
  6. ↑ SUMO1 SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae)
  7. ↑ >Wei W, Yang P, Pang J, Zhang S, Wang Y, Wang M, Dong Z She J, Wang C (Oct 2008). "A stress-dependent SUMO4 sumoylation of its substrate proteins". Biochem Biophys Res Commun 375 (3): 454–459. doi:10.1016/j.bbrc.2008.08.028. PMC 2366111. PMID 18708028. 
  8. ↑ Zhang XD, Goeres J, Zhang H, Yen TJ, Porter AC, Matunis MJ (Mar 2008). "SUMO-2/3 Modification and Binding Regulate the Association of CENP-E with Kinetochores and Progression through Mitosis". Mol Cell 29 (6): 729–41. doi:10.1016/j.molcel.2008.01.013. PMC 2366111. PMID 18374647. 
  9. ↑ Azuma Y, Arnaoutov A, Dasso M (Nov 2003). "SUMO-2/3 regulates topoisomerase II in mitosis". J Cell Biol. 163 (3): 477–87. doi:10.1083/jcb.200304088. PMC 2173648. PMID 14597774. 
  10. ↑ Saitoh H, Hinchey J (Mar 2000). "Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3". J Biol Chem. 275 (9): 6252–8. doi:10.1074/jbc.275.9.6252. PMID 10692421. 
  11. ↑ Matic I, van Hagen M, Schimmel J, et al. (Jan 2008). "In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in vitro to in vivo strategy". Mol Cell Proteomics. 7 (1): 132–44. doi:10.1074/mcp.M700173-MCP200. PMID 17938407. 
  12. ↑ Matic I, Macek B, Hilger M, Walther TC, Mann M (Sep 2008). "Phosphorylation of SUMO-1 occurs in vivo and is conserved through evolution". J Proteome Res. 7 (9): 4050–7. doi:10.1021/pr800368m. PMID 18707152. 
  13. ↑ Gramatikoff K. et al. In Frontiers of Biotechnology and Pharmaceuticals, Science Press (2004) 4: pp.181-210.
  14. ↑ Teng, S.; Luo, H.; Wang, L. (2011). "Predicting protein sumoylation sites from sequence features". Amino Acids 43 (1): 447–455. doi:10.1007/s00726-011-1100-2. PMID 21986959. 
  15. ↑ Ren, J.; Gao, X.; Jin, C.; Zhu, M.; Wang, X.; Shaw, A.; Wen, L.; Yao, X.; Xue, Y. (2009). "Systematic study of protein sumoylation: Development of a site-specific predictor of SUMOsp 2.0". Proteomics 9 (12): 3409–3412. doi:10.1002/pmic.200800646. PMID 19504496. 
  16. ↑ Cheng CH, Lo YH, Liang SS, et al. (Aug 2006). "SUMO modifications control assembly of synaptonemal complex and polycomplex in meiosis of Saccharomyces cerevisiae". Genes Dev. 20 (15): 2067–81. doi:10.1101/gad.1430406. PMC 1536058. PMID 16847351. 
  17. ↑ Pichler A, Knipscheer P, Saitoh H, Sixma TK, Melchior F (Oct 2004). "The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type". Nature Structural & Molecular Biology 11 (10): 984–91. doi:10.1038/nsmb834. PMID 15378033. 
  18. ↑ Mukhopadhyay D, Dasso M (Jun 2007). "Modification in reverse: the SUMO proteases". Trends Biochem. Sci. 32 (6): 286–95. doi:10.1016/j.tibs.2007.05.002. PMID 17499995. 

Further reading

External links

Programs for prediction sumoylation:

Research laboratories

General
N terminus
C terminus
Single specific AAs
Aspartate
Glutamate
  • Transglutamination
  • C-mannosylation
Crosslinks between two AAs
  • Sulfilimine bond
Lysine-Tyrosylquinone
  • Lysine tyrosylquinone (LTQ) formation
Tryptophan-Tryptophylquinone
Three consecutive AAs
(chromophore formation)
  • p-Hydroxybenzylidene-imidazolinone formation
Crosslinks between four AAs
Chaperones/
protein folding
Heat shock proteins/
Chaperonins
Other
Protein targeting
Ubiquitin
Other
See also: posttranslational modification disorders
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
This article is issued from Wikipedia. The text is available under the Creative Commons Attribution/Share Alike; additional terms may apply for the media files.