Small Ubiquitin-like MOdifiers (SUMOs) are a family of 3 proteins (SUMO1,2,3) that are reversibly conjugated to lysine residues of target proteins via a glycine-lysine isopeptide bond (reviewed in Hay 2013, Hannoun et al. 2010, Gareau and Lima 2010, Wilkinson and Henley 2010, Wang and Dasso 2009). Proteomic methods have yielded estimates of hundreds of target proteins. Targets are mostly located in the nucleus and therefore SUMOylation disproportionately affects gene expression. SUMOs are initially translated as proproteins possessing extra amino acid residues at the C-terminus which are removed by the SUMO processing endoproteases SENP1,2,5 (Hay 2007). Different SENPs have significantly different efficiencies with different SUMOs. The processing exposes a glycine residue at the C-terminus that is activated by ATP-dependent thiolation at cysteine-173 of UBA2 in a complex with SAE1, the E1 complex. The SUMO is transferred from E1 to cysteine-93 of a single E2 enzyme, UBC9 (UBE2I). UBC9 with or, in some cases, without an E3 ligase conjugates the glycine C-terminus of SUMO to an epsilon amino group of a lysine residue on the target protein. SUMO2 and SUMO3 may then be further polymerized, forming chains. SUMO1 is unable to form polymers. Conjugated SUMO can act as a biinding site for proteins possessing SUMO interaction motifs (SIMs) and can also directly affect the formation of complexes between the target protein and other proteins. Conjugated SUMOs are removed by cleavage of the isopeptide bond by processing enzymes SENP1,2,3,5. The processing enzymes SENP6 and SENP7 edit chains of SUMO2 and SUMO3.
Lois LM, Lima CD.; ''Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1.''; PubMedEurope PMCScholia
Golebiowski F, Matic I, Tatham MH, Cole C, Yin Y, Nakamura A, Cox J, Barton GJ, Mann M, Hay RT.; ''System-wide changes to SUMO modifications in response to heat shock.''; PubMedEurope PMCScholia
Zhang H, Saitoh H, Matunis MJ.; ''Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex.''; PubMedEurope PMCScholia
Wang J, Chen Y.; ''Role of the Zn(2+) motif of E1 in SUMO adenylation.''; PubMedEurope PMCScholia
Tatham MH, Chen Y, Hay RT.; ''Role of two residues proximal to the active site of Ubc9 in substrate recognition by the Ubc9.SUMO-1 thiolester complex.''; PubMedEurope PMCScholia
Wilkinson KA, Henley JM.; ''Mechanisms, regulation and consequences of protein SUMOylation.''; PubMedEurope PMCScholia
Desterro JM, Rodriguez MS, Kemp GD, Hay RT.; ''Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1.''; PubMedEurope PMCScholia
Werner A, Moutty MC, Möller U, Melchior F.; ''Performing in vitro sumoylation reactions using recombinant enzymes.''; PubMedEurope PMCScholia
Di Bacco A, Ouyang J, Lee HY, Catic A, Ploegh H, Gill G.; ''The SUMO-specific protease SENP5 is required for cell division.''; PubMedEurope PMCScholia
Kim YH, Sung KS, Lee SJ, Kim YO, Choi CY, Kim Y.; ''Desumoylation of homeodomain-interacting protein kinase 2 (HIPK2) through the cytoplasmic-nuclear shuttling of the SUMO-specific protease SENP1.''; PubMedEurope PMCScholia
Olsen SK, Capili AD, Lu X, Tan DS, Lima CD.; ''Active site remodelling accompanies thioester bond formation in the SUMO E1.''; PubMedEurope PMCScholia
Bailey D, O'Hare P.; ''Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1.''; PubMedEurope PMCScholia
Yang XJ, Chiang CM.; ''Sumoylation in gene regulation, human disease, and therapeutic action.''; PubMedEurope PMCScholia
Jentsch S, Psakhye I.; ''Control of nuclear activities by substrate-selective and protein-group SUMOylation.''; PubMedEurope PMCScholia
Da Silva-Ferrada E, Lopitz-Otsoa F, Lang V, Rodríguez MS, Matthiesen R.; ''Strategies to Identify Recognition Signals and Targets of SUMOylation.''; PubMedEurope PMCScholia
Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET.; ''Characterization of a second member of the sentrin family of ubiquitin-like proteins.''; PubMedEurope PMCScholia
Becker J, Barysch SV, Karaca S, Dittner C, Hsiao HH, Berriel Diaz M, Herzig S, Urlaub H, Melchior F.; ''Detecting endogenous SUMO targets in mammalian cells and tissues.''; PubMedEurope PMCScholia
Tatham MH, Matic I, Mann M, Hay RT.; ''Comparative proteomic analysis identifies a role for SUMO in protein quality control.''; PubMedEurope PMCScholia
Gong L, Millas S, Maul GG, Yeh ET.; ''Differential regulation of sentrinized proteins by a novel sentrin-specific protease.''; PubMedEurope PMCScholia
Mikolajczyk J, Drag M, Békés M, Cao JT, Ronai Z, Salvesen GS.; ''Small ubiquitin-related modifier (SUMO)-specific proteases: profiling the specificities and activities of human SENPs.''; PubMedEurope PMCScholia
Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H.; ''In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2.''; PubMedEurope PMCScholia
Itahana Y, Yeh ET, Zhang Y.; ''Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2.''; PubMedEurope PMCScholia
Wang J, Lee B, Cai S, Fukui L, Hu W, Chen Y.; ''Conformational transition associated with E1-E2 interaction in small ubiquitin-like modifications.''; PubMedEurope PMCScholia
Bruderer R, Tatham MH, Plechanovova A, Matic I, Garg AK, Hay RT.; ''Purification and identification of endogenous polySUMO conjugates.''; PubMedEurope PMCScholia
Xu Z, Au SW.; ''Mapping residues of SUMO precursors essential in differential maturation by SUMO-specific protease, SENP1.''; PubMedEurope PMCScholia
Gong L, Yeh ET.; ''Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3.''; PubMedEurope PMCScholia
Hang J, Dasso M.; ''Association of the human SUMO-1 protease SENP2 with the nuclear pore.''; PubMedEurope PMCScholia
Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMedEurope PMCScholia
Gareau JR, Lima CD.; ''The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition.''; PubMedEurope PMCScholia
Flotho A, Melchior F.; ''Sumoylation: a regulatory protein modification in health and disease.''; PubMedEurope PMCScholia
Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT.; ''Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9.''; PubMedEurope PMCScholia
Hannoun Z, Greenhough S, Jaffray E, Hay RT, Hay DC.; ''Post-translational modification by SUMO.''; PubMedEurope PMCScholia
Vertegaal AC, Andersen JS, Ogg SC, Hay RT, Mann M, Lamond AI.; ''Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics.''; PubMedEurope PMCScholia
Wang J, Hu W, Cai S, Lee B, Song J, Chen Y.; ''The intrinsic affinity between E2 and the Cys domain of E1 in ubiquitin-like modifications.''; PubMedEurope PMCScholia
Azuma Y, Tan SH, Cavenagh MM, Ainsztein AM, Saitoh H, Dasso M.; ''Expression and regulation of the mammalian SUMO-1 E1 enzyme.''; PubMedEurope PMCScholia
The SUMO1 precursor has 4 extra residues at the C-terminus which can be removed endoproteolytically by either SENP1, SENP2, or SENP5 (Zheng and Au, 2005, Mikolajczyk et al. 2007). The order of processing activity is: SENP1 greater than SENP2 greater than SENP5 (Mikolajczyk et al. 2007). Both SENP1 and SENP2 shuttle between the nucleus and cytoplasmic and both are predominantly nucleoplasmic (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006).
The UBA2:SAE1 complex catalyzes the formation of a thioester bond between SUMO2 and cysteine-173 of UBA2 (Tatham et al. 2001, Werner et al. 2009). ATP reacts with the C-terminal glycine residue of SUMO2 to yield pyrophosphate and a transient intermediate, SUMO2 adenylate, which then reacts with the thiol group of the cysteine residue on UBA2.
The UBA2:SAE1 complex catalyzes the formation of a thioester bond between SUMO3 and cysteine-173 of UBA2 (Tatham et al. 2001, Werner et al. 2009). ATP reacts with the C-terminal glycine residue of SUMO3 to yield pyrophosphate and a transient intermediate, SUMO3 adenylate, which then reacts with the thiol group of the cysteine residue on UBA2.
The UBA2:SAE1 complex catalyzes the formation of a thioester bond between SUMO1 and cysteine-173 of UBA2 (Desterro et al. 1999, Okuma et al. 1999, Werner et al. 2009, Olsen et al. 2010, Wang and Chen 2010). ATP reacts with the C-terminal glycine residue of SUMO1 to yield pyrophosphate and a transient intermediate, SUMO1 adenylate, which then reacts with the thiol group of the cysteine residue on UBA2.
The SUMO2 precursor has 2 extra residues at the C-terminus which can be removed endoproteolytically by SENP1, SENP2, or SENP5 (Zheng and Au, 2005, Gong and Yeh 2006, Mikolajczyk et al. 2007). The order of processing activity is: SENP1 greater than SENP2 greater than SENP5 (Mikolajczyk et al. 2007). SENP2 and SENP5 have highest activity on SUMO2, however the processing activity of SENP1 is higher overall (Mikolajczyk et al. 2007). SENP1 and SENP2 shuttle between the nucleus and cytosol and are predominantly nuclear (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006). SENP5 is located in the nucleolus (Di Bacco et al. 2006, Gong and Yeh 2006).
The SUMO3 precursor has 11 extra residues at the C-terminus which can be removed endoproteolytically by SENP1, SENP2, or SENP5 (Zheng and Au, 2005, Gong and Yeh 2006, Mikolajczyk et al. 2007). The order of processing activity is: SENP1 greater than SENP2 greater than SENP5 (Mikolajczyk et al. 2007). Overall, processing of SUMO3 is the lowest of any SUMO (Mikolajczyk et al. 2007). SENP1 and SENP2 shuttle between the nucleus and cytosol and are predominantly nuclear (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006). SENP5 is located in the nucleolus (Di Bacco et al. 2006, Gong and Yeh 2006).
SUMO1 is transferred from cysteine-173 of UBA2 to cysteine-93 of UBC9 (UBE2I) in a transthiolation reaction (Desterro et al. 1999, Okuma et al. 1999, Tatham et al. 2003, Lois and Lima 2005, Wang et al. 2007, Werner et al. 2009). The UbL domain of E1 recruits E2 into proximity for the transfer of SUMO (Lois and Lima 2005, Wang et al. 2009),
SUMOs are initially translated as proproteins possessing extra amino acid residues at the C-terminus which are removed by the SUMO processing endoproteases SENP1,2,5 (Hay 2007). Different SENPs have significantly different efficiencies with different SUMOs. The processing exposes a glycine residue at the C-terminus that is activated by ATP-dependent thiolation at cysteine-173 of UBA2 in a complex with SAE1, the E1 complex. The SUMO is transferred from E1 to cysteine-93 of a single E2 enzyme, UBC9 (UBE2I). UBC9 with or, in some cases, without an E3 ligase conjugates the glycine C-terminus of SUMO to an epsilon amino group of a lysine residue on the target protein. SUMO2 and SUMO3 may then be further polymerized, forming chains. SUMO1 is unable to form polymers.
Conjugated SUMO can act as a biinding site for proteins possessing SUMO interaction motifs (SIMs) and can also directly affect the formation of complexes between the target protein and other proteins.
Conjugated SUMOs are removed by cleavage of the isopeptide bond by processing enzymes SENP1,2,3,5. The processing enzymes SENP6 and SENP7 edit chains of SUMO2 and SUMO3.
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