SUMO protein

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In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes written sumoylation). 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]

Contents

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 HSUMO1 1A5R nmr ribbons.png
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 HSUMO1 1A5R nmr spheres.png
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, 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 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 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 (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 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:

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 SAE1 and SAE2). 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, [19] 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. 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

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Post-translational modification</span> Biological processes

Post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes translating mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">Protein inhibitor of activated STAT</span>

Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with.

Abgent is a global biotechnology company based in San Diego, California, US with offices in Maidenhead, UK and Suzhou, China and distributors around the world. Abgent develops antibodies and related agents to study proteins involved in cellular function and disease. Abgent's antibodies target key areas of research including autophagy, neuroscience, cancer, stem cells and more. Abgent was acquired in 2011 by WuXi AppTec, a global pharmaceutical, biopharmaceutical, and medical device outsourcing company with operations in China and the United States.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

<span class="mw-page-title-main">SUMO1</span> Protein-coding gene in the species Homo sapiens

Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the SUMO1 gene.

<span class="mw-page-title-main">UBE2I</span> Protein-coding gene in the species Homo sapiens

SUMO-conjugating enzyme UBC9 is an enzyme that in humans is encoded by the UBE2I gene. It is also sometimes referred to as "ubiquitin conjugating enzyme E2I" or "ubiquitin carrier protein 9", even though these names do not accurately describe its function.

<span class="mw-page-title-main">PIAS1</span> Protein-coding gene in the species Homo sapiens

E3 SUMO-protein ligase PIAS1 is an enzyme that in humans is encoded by the PIAS1 gene.

<span class="mw-page-title-main">SUMO3</span> Protein-coding gene in the species Homo sapiens

Small ubiquitin-related modifier 3 is a protein that in humans is encoded by the SUMO3 gene.

<span class="mw-page-title-main">SENP3</span> Protein-coding gene in humans

SUMO1/sentrin/SMT3 specific peptidase 3, also known as SENP3, is a protein which in humans is encoded by the SENP3 gene.

<span class="mw-page-title-main">SENP1</span> Protein-coding gene in humans

Sentrin-specific protease 1 is an enzyme that in humans is encoded by the SENP1 gene.

<span class="mw-page-title-main">SENP6</span> Protein-coding gene in the species Homo sapiens

Sentrin-specific protease 6 is an enzyme that in humans is encoded by the SENP6 gene.

<span class="mw-page-title-main">RNF128</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase RNF128 is an enzyme that in humans is encoded by the RNF128 gene.

<span class="mw-page-title-main">UBA2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known as SUMO-activating enzyme subunit 2 (SAE2) is an enzyme that in humans is encoded by the UBA2 gene.

<span class="mw-page-title-main">Ubiquitin-like protein</span> Family of small proteins

Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation.

<span class="mw-page-title-main">C8orf34</span> Gene of the species Homo sapiens

C8orf34 is a protein that, in Homo sapiens, is encoded by the C8orf34 gene. Aliases for C8orf34 include vestibule-1 or VEST-1. Within the cell, C8orf34 is localized to the nucleus and nucleoli where it may play a role in the regulation of gene expression as well as the cell cycle.

Arabidopsis SUMO-conjugation enzyme (AtSCE1) is an enzyme that is a member of the small ubiquitin-like modifier (SUMO) post-translational modification pathway. This process, and the SCE1 enzyme with it, is highly conserved across eukaryotes yet absent in prokaryotes. In short, this pathway results in the attachment of a small polypeptide through an isopeptide bond between modifying enzyme and the ε-amino group of a lysine residue in the substrate. In plants, the 160 amino acid SCE1 enzyme was first characterized in 2003. One functional gene copy, SCE1a, was found on chromosomes 3.

References

  1. ↑ Hay RT (April 2005). "SUMO: a history of modification". Molecular Cell. 18 (1): 1–12. doi: 10.1016/j.molcel.2005.03.012 . PMID   15808504.
  2. ↑ Matunis MJ, Coutavas E, Blobel G (December 1996). "A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex". The Journal of Cell Biology. 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 (January 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. S2CID   17819277.
  4. ↑ Cheng TS, Chang LK, Howng SL, Lu PJ, Lee CI, Hong YR (February 2006). "SUMO-1 modification of centrosomal protein hNinein promotes hNinein nuclear localization" (PDF). Life Sciences. 78 (10): 1114–20. doi:10.1016/j.lfs.2005.06.021. PMID   16154161.
  5. ↑ Gill G (October 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 MH, Dong Z, She JX, Wang CY (October 2008). "A stress-dependent SUMO4 SUMOylation of its substrate proteins". Biochemical and Biophysical Research Communications. 375 (3): 454–9. doi:10.1016/j.bbrc.2008.08.028. PMID   18708028.
  8. ↑ Zhang XD, Goeres J, Zhang H, Yen TJ, Porter AC, Matunis MJ (March 2008). "SUMO-2/3 modification and binding regulate the association of CENP-E with kinetochores and progression through mitosis". Molecular Cell. 29 (6): 729–41. doi:10.1016/j.molcel.2008.01.013. PMC   2366111 . PMID   18374647.
  9. ↑ Azuma Y, Arnaoutov A, Dasso M (November 2003). "SUMO-2/3 regulates topoisomerase II in mitosis". The Journal of Cell Biology. 163 (3): 477–87. doi:10.1083/jcb.200304088. PMC   2173648 . PMID   14597774.
  10. ↑ Saitoh H, Hinchey J (March 2000). "Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3". The Journal of Biological Chemistry. 275 (9): 6252–8. doi: 10.1074/jbc.275.9.6252 . PMID   10692421.
  11. ↑ Matic I, van Hagen M, Schimmel J, Macek B, Ogg SC, Tatham MH, Hay RT, Lamond AI, Mann M, Vertegaal AC (January 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". Molecular & Cellular Proteomics. 7 (1): 132–44. doi: 10.1074/mcp.M700173-MCP200 . PMC   3840926 . PMID   17938407.
  12. ↑ Matic I, Macek B, Hilger M, Walther TC, Mann M (September 2008). "Phosphorylation of SUMO-1 occurs in vivo and is conserved through evolution". Journal of Proteome Research. 7 (9): 4050–7. doi:10.1021/pr800368m. PMID   18707152.
  13. 1 2 Jalal D, Chalissery J, Hassan AH (2017). "Genome maintenance in Saccharomyces cerevisiae: the role of SUMO and SUMO-targeted ubiquitin ligases". Nucleic Acids Res. 45 (5): 2242–2261. doi:10.1093/nar/gkw1369. PMC   5389695 . PMID   28115630.
  14. 1 2 Geiss-Friedlander, Ruth; Melchior, Frauke (December 2007). "Concepts in sumoylation: a decade on". Nature Reviews Molecular Cell Biology. 8 (12): 947–956. doi:10.1038/nrm2293. ISSN   1471-0080. PMID   18000527. S2CID   30462190.
  15. ↑ Gramatikoff K. et al. In Frontiers of Biotechnology and Pharmaceuticals, Science Press (2004) 4: pp.181-210.
  16. ↑ Teng S, Luo H, Wang L (July 2012). "Predicting protein SUMOylation sites from sequence features". Amino Acids. 43 (1): 447–55. doi:10.1007/s00726-011-1100-2. PMID   21986959. S2CID   14360760.
  17. ↑ Ren, Jian; Gao, Xinjiao; Jin, Changjiang; Zhu, Mei; Wang, Xiwei; Shaw, Andrew; Wen, Longping; Yao, Xuebiao; Xue, Yu (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. S2CID   4900031.
  18. ↑ Beauclair G, Bridier-Nahmias A, Zagury JF, Saïb A, Zamborlini A (November 2015). "JASSA: a comprehensive tool for prediction of SUMOylation sites and SIMs". Bioinformatics. 31 (21): 3483–91. doi: 10.1093/bioinformatics/btv403 . PMID   26142185.
  19. ↑ Cheng CH, Lo YH, Liang SS, Ti SC, Lin FM, Yeh CH, Huang HY, Wang TF (August 2006). "SUMO modifications control assembly of synaptonemal complex and polycomplex in meiosis of Saccharomyces cerevisiae". Genes & Development. 20 (15): 2067–81. doi:10.1101/gad.1430406. PMC   1536058 . PMID   16847351.
  20. ↑ Pichler A, Knipscheer P, Saitoh H, Sixma TK, Melchior F (October 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. S2CID   28085778.
  21. ↑ Mukhopadhyay D, Dasso M (June 2007). "Modification in reverse: the SUMO proteases". Trends in Biochemical Sciences. 32 (6): 286–95. doi:10.1016/j.tibs.2007.05.002. PMID   17499995.
  22. ↑ Burgess, Richard; Deutscher, Murray (2009). "Chapter 17 Refolding Solubilized Inclusion Body Proteins". Guide to Protein Purification, 2nd Edition. Methods in Enzymology. Vol. 463 (2nd ed.). pp. 259–282. doi:10.1016/S0076-6879(09)63017-2. ISBN   978-0-12-374536-1. PMID   19892177.
  23. 1 2 3 Kuo, Dennis; Nie, Minghua; Courey, Albert (2014). Protein Affinity Tags. Methods in Molecular Biology (Methods and Protocols). New York, NY: Humana Press. pp. 71–80. ISBN   978-1-4939-1034-2.

Further reading

Programs for prediction SUMOylation:

Research laboratories

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