Small ubiquitin-related modifier 1

Small ubiquitin-like modifier 1
PDB rendering based on 1a5r.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1A5R​, 1TGZ​, 1WYW​, 1Y8R​, 1Z5S​, 2ASQ​, 2BF8​, 2G4D​, 2IO2​, 2IY0​, 2IY1​, 2KQS​, 2LAS​, 2MW5​, 2PE6​, 2UYZ​, 2VRR​, 3KYC​, 3KYD​, 3RZW​, 3UIP​, 4WJN​, 4WJO​, 4WJP​, 4WJQ​
Identifiers
Symbols	SUMO1 ; DAP1; GMP1; OFC10; PIC1; SENP2; SMT3; SMT3C; SMT3H3; UBL1
External IDs	OMIM: 601912 MGI: 1197010 HomoloGene: 2514 GeneCards: SUMO1 Gene
Gene ontology Molecular function • protein binding • transcription factor binding • potassium channel regulator activity • SUMO transferase activity • ubiquitin protein ligase binding • ion channel binding • poly(A) RNA binding Cellular component • heterochromatin • fibrillar center • XY body • nucleus • nuclear pore • nucleoplasm • nucleolus • cytoplasm • plasma membrane • voltage-gated potassium channel complex • PML body • nuclear speck • dendrite • nuclear membrane • synapse Biological process • DNA repair • viral process • protein sumoylation • cytokine-mediated signaling pathway • PML body organization • positive regulation of protein complex assembly • regulation of protein stability • positive regulation of proteasomal ubiquitin-dependent protein catabolic process • regulation of protein localization • negative regulation of DNA binding • negative regulation of sequence-specific DNA binding transcription factor activity • post-translational protein modification • cellular protein metabolic process • negative regulation of action potential • negative regulation of transcription, DNA-templated • palate development • interferon-gamma-mediated signaling pathway • regulation of interferon-gamma-mediated signaling pathway • regulation of cardiac muscle cell contraction • protein localization to nuclear pore • positive regulation of calcium-transporting ATPase activity • negative regulation of delayed rectifier potassium channel activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7341	22218
Ensembl	ENSG00000116030	ENSMUSG00000026021
UniProt	P63165	P63166
RefSeq (mRNA)	NM_001005781	NM_009460
RefSeq (protein)	NP_001005781	NP_033486
Location (UCSC)	Chr 2: 202.21 – 202.24 Mb	Chr 1: 59.59 – 59.67 Mb
PubMed search

Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the SUMO1 gene.^[1][2]

This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It functions in a manner similar to ubiquitin in that it is bound to target proteins as part of a post-translational modification system. However, unlike ubiquitin, which targets proteins for degradation, this protein is involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability. It is not active until the last four amino acids of the carboxy-terminus have been cleaved off. Several pseudogenes have been reported for this gene. Alternate transcriptional splice variants encoding different isoforms have been characterized.^[3]

Most cleft genes have a sumoylation component .^[4] Analysis of chromosomal anomalies in patients has led to the identification and confirmation of SUMO1 as a cleft lip and palate locus.^[5]

Interactions

Small ubiquitin-related modifier 1 has been shown to interact with SAE2,^[6][7] Death-associated protein 6,^[8][9][10] Fas receptor,^[2][9] Sp1 transcription factor,^[11] PIAS1,^[12][13] Thymine-DNA glycosylase,^[14][15] UBE2I,^{[6][14][16][17]} TNFRSF1A,^[2][18] P53,^[10][14] TOP2B,^[19] TOP2A,^[19] DNMT3B,^[20] Promyelocytic leukemia protein,^[8][21] and C22orf25.^[22]

SUMO1 Role in the Heart

Heart failure is a process by which the heart’s pumping ability is significantly weakened, so that the body is unable to get adequate circulation. A weakened heart results in symptoms of fatigue, decreased exercise tolerance and shortness of breath. Patients with heart failure have a significantly increased risk of death compared to people with normal heart function. Heart failure is a major public health concern, as its incidence is on the rise worldwide, and is a leading cause of death in developed nations ^[23]

SUMO 1 is a key component in cardiac function, since it helps regulate calcium homeostasis in the mitochondria of heart cells. SUMO 1 is associated with another essential cardiac protein called sarco/endoplasmic reticulum Ca2+ ATPase, or SERCA2A. SERCA is a transmembrane protein located in the sarcoplasmic reticulum of cardiac cells. Its main function is to regulate the discharge and uptake of intracellular calcium between the cytosol and the lumen of the sarcoplasmic reticulum. Calcium is an essential factor for the development of cardiac myocyte contraction and relaxation. Thus, the management of intracellular calcium homeostasis by SERCA2A is critical for overall cardiac performance.^[24] Normally, SUMO 1 activates and stabilizes SERCA2A by binding at lysine resides 480 and 585. The interaction between SUMO 1 and SERCA2A is crucial for regulating calcium levels inside cardiac myocytes. Reduction in SUMO 1 protein reduces SERCA2A, and thus efficient calcium handling in patients with failing hearts ^[25]

SUMO 1 as a Drug Target

SUMO 1 may be an important therapeutic target to help improve cardiac performance in patients with heart failure. In a mouse model, the introduction of SUMO 1 through gene therapy was associated with improved activity of SERCA2A, which resulted in improved cardiac function through an augmentation of cardiac contractility.^[25] Furthermore, overexpression of SUMO 1 resulted in accelerated calcium uptake, providing further evidence regarding its importance in maintaining adequate calcium levels in heart cells. This particular heart protein may be an exciting and novel target for heart failure treatment in the future.^[25]

See also

• SENP6

References

1. Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ (January 1997). "UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins". Genomics 36 (2): 271–9. doi:10.1006/geno.1996.0462. PMID 8812453.
2. Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET (Dec 1996). "Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin". J Immunol 157 (10): 4277–81. PMID 8906799.
3. "Entrez Gene: SUMO1 SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae)".
4. Pauws E, Stanier P (December 2007). "FGF signalling and SUMO modification: new players in the aetiology of cleft lip and/or palate". Trends Genet. 23 (12): 631–40. doi:10.1016/j.tig.2007.09.002. PMID 17981355.
5. Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews Genetics (12) 167-178.
6. Tatham, Michael H; Kim Suhkmann; Yu Bin; Jaffray Ellis; Song Jing; Zheng Jian; Rodriguez Manuel S; Hay Ronald T; Chen Yuan (August 2003). "Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation". Biochemistry (United States) 42 (33): 9959–69. doi:10.1021/bi0345283. ISSN 0006-2960. PMID 12924945.
7. Gong, L; Li B; Millas S; Yeh E T (April 1999). "Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex". FEBS Lett. (NETHERLANDS) 448 (1): 185–9. doi:10.1016/S0014-5793(99)00367-1. ISSN 0014-5793. PMID 10217437.
8. Lin, Ding-Yen; Shih Hsiu-Ming (July 2002). "Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration". J. Biol. Chem. (United States) 277 (28): 25446–56. doi:10.1074/jbc.M200633200. ISSN 0021-9258. PMID 11948183.
9. Ryu, S W; Chae S K; Kim E (Dec 2000). "Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9". Biochem. Biophys. Res. Commun. (UNITED STATES) 279 (1): 6–10. doi:10.1006/bbrc.2000.3882. ISSN 0006-291X. PMID 11112409.
10. Ivanchuk, Stacey M; Mondal Soma; Rutka James T (June 2008). "p14ARF interacts with DAXX: effects on HDM2 and p53". Cell Cycle (United States) 7 (12): 1836–50. doi:10.4161/cc.7.12.6025. PMID 18583933.
11. Wang, Yi-Ting; Chuang Jian-Ying; Shen Meng-Ru; Yang Wen-Bin; Chang Wen-Chang; Hung Jan-Jong (July 2008). "Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process". J. Mol. Biol. (England) 380 (5): 869–85. doi:10.1016/j.jmb.2008.05.043. PMID 18572193.
12. Lee, Byoung-Hee; Yoshimatsu Kumiko; Maeda Akihiko; Ochiai Kazuhiko; Morimatsu Masami; Araki Koichi; Ogino Michiko; Morikawa Shigeru; Arikawa Jiro (Dec 2003). "Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules". Virus Res. (Netherlands) 98 (1): 83–91. doi:10.1016/j.virusres.2003.09.001. ISSN 0168-1702. PMID 14609633.
13. Kahyo, T; Nishida T; Yasuda H (September 2001). "Involvement of PIAS1 in the sumoylation of tumor suppressor p53". Mol. Cell (United States) 8 (3): 713–8. doi:10.1016/S1097-2765(01)00349-5. ISSN 1097-2765. PMID 11583632.
14. Minty, A; Dumont X; Kaghad M; Caput D (November 2000). "Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif". J. Biol. Chem. (UNITED STATES) 275 (46): 36316–23. doi:10.1074/jbc.M004293200. ISSN 0021-9258. PMID 10961991.
15. Hardeland, Ulrike; Steinacher Roland; Jiricny Josef; Schär Primo (March 2002). "Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover". EMBO J. (England) 21 (6): 1456–64. doi:10.1093/emboj/21.6.1456. ISSN 0261-4189. PMC 125358. PMID 11889051.
16. Ewing, Rob M; Chu Peter, Elisma Fred, Li Hongyan, Taylor Paul, Climie Shane, McBroom-Cerajewski Linda, Robinson Mark D, O'Connor Liam, Li Michael, Taylor Rod, Dharsee Moyez, Ho Yuen, Heilbut Adrian, Moore Lynda, Zhang Shudong, Ornatsky Olga, Bukhman Yury V, Ethier Martin, Sheng Yinglun, Vasilescu Julian, Abu-Farha Mohamed, Lambert Jean-Philippe, Duewel Henry S, Stewart Ian I, Kuehl Bonnie, Hogue Kelly, Colwill Karen, Gladwish Katharine, Muskat Brenda, Kinach Robert, Adams Sally-Lin, Moran Michael F, Morin Gregg B, Topaloglou Thodoros, Figeys Daniel (2007). "Large-scale mapping of human protein–protein interactions by mass spectrometry". Mol. Syst. Biol. (England) 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. Cite uses deprecated parameter |coauthors= (help)
17. Shen, Z; Pardington-Purtymun P E; Comeaux J C; Moyzis R K; Chen D J (October 1996). "Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system". Genomics (UNITED STATES) 37 (2): 183–6. doi:10.1006/geno.1996.0540. ISSN 0888-7543. PMID 8921390.
18. Liou, M L; Liou H C (April 1999). "The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis". J. Biol. Chem. (UNITED STATES) 274 (15): 10145–53. doi:10.1074/jbc.274.15.10145. ISSN 0021-9258. PMID 10187798.
19. Mao, Y; Desai S D; Liu L F (August 2000). "SUMO-1 conjugation to human DNA topoisomerase II isozymes". J. Biol. Chem. (UNITED STATES) 275 (34): 26066–73. doi:10.1074/jbc.M001831200. ISSN 0021-9258. PMID 10862613.
20. Kang, E S; Park C W; Chung J H (Dec 2001). "Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1". Biochem. Biophys. Res. Commun. (United States) 289 (4): 862–8. doi:10.1006/bbrc.2001.6057. ISSN 0006-291X. PMID 11735126.
21. Kamitani, T; Nguyen H P; Kito K; Fukuda-Kamitani T; Yeh E T (February 1998). "Covalent modification of PML by the sentrin family of ubiquitin-like proteins". J. Biol. Chem. (UNITED STATES) 273 (6): 3117–20. doi:10.1074/jbc.273.6.3117. ISSN 0021-9258. PMID 9452416.
22. "Molecular Interaction Database".
23. Schwartz, R. J., & Yeh, E. T. (2012). Weighing in on Heart Failure: The Role of SERCA2a SUMOylation. Circulation research, 110(2), 198-199.
24. Periasamy, M., & Huke, S. (2001). SERCA Pump Level is a Critical Determinant of Ca< sup> 2+ Homeostasis and Cardiac Contractility. Journal of molecular and cellular cardiology, 33(6), 1053-1063.
25. Kho, C., Lee, A., Jeong, D., Oh, J. G., Chaanine, A. H., Kizana, E., & Hajjar, R. J. (2011). SUMO1-dependent modulation of SERCA2a in heart failure" Nature 477(7366), 601-605.

External links

• SUMO1 human gene location in the UCSC Genome Browser.
• SUMO1 human gene details in the UCSC Genome Browser.

Further reading

• Cookson MR (2003). "Pathways to Parkinsonism". Neuron 37 (1): 7–10. doi:10.1016/S0896-6273(02)01166-2. PMID 12526767.
• Boddy MN, Howe K, Etkin LD, et al. (1996). "PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia". Oncogene 13 (5): 971–82. PMID 8806687.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Shen Z, Pardington-Purtymun PE, Comeaux JC, et al. (1997). "Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system". Genomics 37 (2): 183–6. doi:10.1006/geno.1996.0540. PMID 8921390.
• Matunis MJ, Coutavas E, Blobel G (1997). "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.
• Mahajan R, Delphin C, Guan T, et al. (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.
• Lapenta V, Chiurazzi P, van der Spek P, et al. (1997). "SMT3A, a human homologue of the S. cerevisiae SMT3 gene, maps to chromosome 21qter and defines a novel gene family". Genomics 40 (2): 362–6. doi:10.1006/geno.1996.4556. PMID 9119407.
• Kamitani T, Nguyen HP, Yeh ET (1997). "Preferential modification of nuclear proteins by a novel ubiquitin-like molecule". J. Biol. Chem. 272 (22): 14001–4. doi:10.1074/jbc.272.22.14001. PMID 9162015.
• Mahajan R, Gerace L, Melchior F (1998). "Molecular Characterization of the SUMO-1 Modification of RanGAP1 and Its Role in Nuclear Envelope Association". J. Cell Biol. 140 (2): 259–70. doi:10.1083/jcb.140.2.259. PMC 2132567. PMID 9442102.
• Howe K, Williamson J, Boddy N, et al. (1998). "The ubiquitin-homology gene PIC1: characterization of mouse (Pic1) and human (UBL1) genes and pseudogenes". Genomics 47 (1): 92–100. doi:10.1006/geno.1997.5091. PMID 9465300.
• Bayer P, Arndt A, Metzger S, et al. (1998). "Structure determination of the small ubiquitin-related modifier SUMO-1". J. Mol. Biol. 280 (2): 275–86. doi:10.1006/jmbi.1998.1839. PMID 9654451.
• Desterro JM, Rodriguez MS, Hay RT (1998). "SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation". Mol. Cell 2 (2): 233–9. doi:10.1016/S1097-2765(00)80133-1. PMID 9734360.
• Juo P, Kuo CJ, Yuan J, Blenis J (1998). "Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade". Curr. Biol. 8 (18): 1001–8. doi:10.1016/S0960-9822(07)00420-4. PMID 9740801.
• Kamitani T, Kito K, Nguyen HP, et al. (1998). "Identification of three major sentrinization sites in PML". J. Biol. Chem. 273 (41): 26675–82. doi:10.1074/jbc.273.41.26675. PMID 9756909.
• Duprez E, Saurin AJ, Desterro JM, et al. (1999). "SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation". J. Cell. Sci. 112 (3): 381–93. PMID 9885291.
• Chen A, Mannen H, Li SS (1999). "Characterization of mouse ubiquitin-like SMT3A and SMT3B cDNAs and gene/pseudogenes". Biochem. Mol. Biol. Int. 46 (6): 1161–74. doi:10.1080/15216549800204722. PMID 9891849.
• Okuma T, Honda R, Ichikawa G, et al. (1999). "In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2". Biochem. Biophys. Res. Commun. 254 (3): 693–8. doi:10.1006/bbrc.1998.9995. PMID 9920803.
• Liou ML, Liou HC (1999). "The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis". J. Biol. Chem. 274 (15): 10145–53. doi:10.1074/jbc.274.15.10145. PMID 10187798.