Disease relevance of SUMO2

• A truncated human SUMO-2 protein that contains residues 9-93 was expressed in Escherichia coli and crystallized in two different unit cells, with dimensions of a=b=75.25 A, c=29.17 A and a=b=74.96 A, c=33.23 A, both belonging to the rhombohedral space group R3 [1].
• IE2 was efficiently modified by SUMO-1 or SUMO-2 in cotransfected cells and in cells infected with a recombinant adenovirus expressing HCMV IE2, although the level of modification was much lower in HCMV-infected cells [2].

High impact information on SUMO2

• PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes [3].
• Topoisomerase II was modified exclusively by SUMO-2/3 during mitosis under normal circumstances, although we observed conjugation of topoisomerase II to SUMO-1 in extracts with exogenous SUMO-1 protein [4].
• SUMO-2/3 regulates topoisomerase II in mitosis [4].
• NXP-2 association with SUMO-2 depends on lysines required for transcriptional repression [5].
• Here we report conjugation of two other members of the SUMO protein family, SUMO-2 and SUMO-3, and provide evidence that this post-translational modification negatively affects transcriptional activity of c-Myb [6].

Biological context of SUMO2

• Using yeast two-hybrid system, bioinformatics, and NMR spectroscopy we define a common SUMO-interacting motif (SIM) and map its binding surfaces on SUMO1 and SUMO2 [7].
• We further showed that both sentrin-1 and sentrin-2 could covalently modify RanGAP1, a Ran GTPase-activating protein critically involved in nuclear transport [8].
• Together, these findings demonstrate that mammalian SUMO-1 shows patterns of utilization that are clearly discrete from the patterns of SUMO-2 and -3 throughout the cell cycle, arguing that it is functionally distinct and specifically regulated in vivo [9].
• SUMO-2 and SUMO-3 localized to chromosome earlier and accumulated gradually during telophase [9].
• The protein-coding sequence of the SUMO-1 gene is interrupted by four introns, while those of SUMO-2 and SUMO-3 genes are interrupted by three introns [10].

Anatomical context of SUMO2

• The ability of sentrin-2 to conjugate to other proteins was tested by expressing hemagglutinin epitope-tagged sentrin-2 in COS cells [8].
• Whereas SUMO-2 and -3 showed very similar distributions throughout the nucleoplasm, SUMO-1 was uniquely distributed to the nuclear envelope and to the nucleolus [9].
• A stable HeLa cell line expressing His6-tagged SUMO-2 was established and used to label and purify novel endogenous SUMO-2 target proteins [11].
• Here, stable cell lines overexpressing processed forms of SUMO-2/3 (SUMO-2/3GG) as well as their non-conjugatable derivatives, SUMO-2/3DeltaGG, were established [12].

Associations of SUMO2 with chemical compounds

• We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229 [13].
• Additionally, siRNA-mediated repression of SUMO-2 significantly inhibits the growth of both androgen-dependent and -independent LNCaP cells [14].
• In addition, H(2)O(2) treatment of untransfected cells caused an increase in p53 sumoylation by SUMO-2/3, whereas that by SUMO-1 remained unchanged [12].
• Distinct and Overlapping Sets of SUMO-1 and SUMO-2 Target Proteins Revealed by Quantitative Proteomics [15].

Physical interactions of SUMO2

• To determine the basis for this substrate specificity, we have determined the crystal structure of SENP1 in isolation and in a transition-state complex with SUMO-2 [16].

Enzymatic interactions of SUMO2

• PIAS-3 protein was identified as a new c-Myb-specific SUMO-E3 ligase that both catalyzes conjugation of SUMO-2/3 proteins to c-Myb and exerts a negative effect on c-Myb-induced reporter gene activation [6].

Regulatory relationships of SUMO2

• Expression of SUMO-2/3 Induced Senescence through p53- and pRB-mediated Pathways [12].
• The senescence pathway protein p21 was up-regulated in cells overexpressing SUMO-2/3GG [12].
• These results argue that PIAS-3 SUMO-E3 ligase plays a critical role in stress-induced conjugation of SUMO-2/3 to c-Myb [6].

Other interactions of SUMO2

• Substitutions within this area specifically and dramatically affected the ability of both SUMO2 and SUMO1 to inhibit transcription and revealed that the positively charged nature of the key basic residues is the main feature responsible for their functional role [17].
• Inspection of the SUMO-2 and SUMO-3 sequences indicates that they both contain the sequence psiKXE, which represents the consensus SUMO modification site [18].
• The interface between SUMO-2 and SENP1 has a relatively poor complementarity, and most of the recognition is determined by interaction between the conserved C-terminus of SUMO-2 and the cleft in the protease [16].
• Both p53 and pRB were found to be modified by SUMO-2/3 [12].
• In contrast, cells overexpressing non-conjugatable forms of SUMO-2/3DeltaGG showed neither an apparent senescent phenotype nor elevated p21 [12].

Analytical, diagnostic and therapeutic context of SUMO2

• Western blot analysis showed that sentrin-2 could be transferred to other proteins in a pattern similar to that of sentrin-1 conjugation and had similar C-terminal processing [8].
• Northern blot analysis showed that the sentrin-2 message was expressed in all tissues, but was barely detectable in the liver and placenta [8].
• Site-directed mutagenesis studies showed that Lys-386 of p53, the SUMO-1 modification site, is also the modification site for SUMO-2/3 [12].
• Confocal immunofluorescence microscopy indicated that in unstressed cells sumo-1 targeted nuclear proteins, whereas sumo-2/3 targeted proteins in both nuclei and cytoplasm [19].
• SART1 was confirmed by immunoblotting to have both SUMO-1- and SUMO-2-linked forms at similar levels [15].

References