Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SUMO proteins belong to the Ubiquitin-like protein family, all sharing a common fold and a similar mechanism of conjugation to target polypeptides. SUMO is ubiquitous in all eukaryotes and participates in many crucial pathways. Native SUMO proteins are highly soluble, a property that is exploited in biotechnology. Moreover, SUMO regulates the solubility of aggregation-prone proteins in neurodegenerative disorders. Despite these properties, we show here that human SUMO1, SUMO2, and SUMO3 proteins are at risk of aggregation into amyloid structures if their native conformation is perturbed. Aggregation is mediated by specific regions, which overlap with SUMO functional interfaces, illustrating a competition between function and aggregation. Aggregation of SUMOs might have important physiological implications because disruption of the SUMO pathway is lethal in different organisms. It appears that functional constraints make it difficult to avoid the competition between productive folding and deleterious aggregation in globular proteins, even for essential polypeptides.
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PMID:Native structure protects SUMO proteins from aggregation into amyloid fibrils. 2255 98

Mx proteins are evolutionarily conserved dynamin-like large GTPases involved in viral resistance triggered by types I and III interferons. The human MxA is a cytoplasmic protein that confers resistance to a large number of viruses. The MxA protein is also known to self-assembly into high molecular weight homo-oligomers. Using a yeast two-hybrid screen, we identified 27 MxA binding partners, some of which are related to the SUMOylation machinery. The interaction of MxA with Small-Ubiquitin MOdifier 1 (SUMO1) and Ubiquitin conjugating enzyme 9 (Ubc9) was confirmed by co-immunoprecipitation and co-localization by confocal microscopy. We identified one SUMO conjugation site at lysine 48 and two putative SUMO interacting motifs (SIMa and SIMb). We showed that MxA interacts with the EIL loop of SUMO1 in a SIM-independent manner via its CID-GED domain. The yeast two-hybrid mapping also revealed that Ubc9 binds to the MxA GTPase domain. Mutation in the putative SIMa and SIMb, which are located in the GTPase binding domain, reduced MxA antiviral activity. In addition, we showed that MxA can be conjugated to SUMO2 or SUMO3 at lysine 48 and that the SUMOylation-deficient mutant of MxA (MxAK48R) retained its capacity to oligomerize and to inhibit Vesicular Stomatitis Virus (VSV) and Influenza A Virus replication, suggesting that MxA SUMOylation is not essential for its antiviral activity.
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PMID:MxA interacts with and is modified by the SUMOylation machinery. 2544 5

SUMOylation is a form of post-translational modification involving covalent attachment of SUMO (Small Ubiquitin-like Modifier) polypeptides to specific lysine residues in the target protein. In human cells, there are four SUMO proteins, SUMO1-4, with SUMO2 and SUMO3 forming a closely related subfamily. SUMO2/3, in contrast to SUMO1, are predominantly involved in the cellular response to certain stresses, including heat shock. Substantial evidence from studies in yeast has shown that SUMOylation plays an important role in the regulation of DNA replication and repair. Here, we report a proteomic analysis of proteins modified by SUMO2 in response to DNA replication stress in S phase in human cells. We have identified a panel of 22 SUMO2 targets with increased SUMOylation during DNA replication stress, many of which play key functions within the DNA replication machinery and/or in the cellular response to DNA damage. Interestingly, POLD3 was found modified most significantly in response to a low dose aphidicolin treatment protocol that promotes common fragile site (CFS) breakage. POLD3 is the human ortholog of POL32 in budding yeast, and has been shown to act during break-induced recombinational repair. We have also shown that deficiency of POLD3 leads to an increase in RPA-bound ssDNA when cells are under replication stress, suggesting that POLD3 plays a role in the cellular response to DNA replication stress. Considering that DNA replication stress is a source of genome instability, and that excessive replication stress is a hallmark of pre-neoplastic and tumor cells, our characterization of SUMO2 targets during a perturbed S-phase should provide a valuable resource for future functional studies in the fields of DNA metabolism and cancer biology.
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PMID:Proteome-wide analysis of SUMO2 targets in response to pathological DNA replication stress in human cells. 2549 29

SUMOylation, the covalent binding of Small Ubiquitin-like Modifier (SUMO) to target proteins, is a posttranslational modification that regulates critical cellular processes in eukaryotes. In insects, SUMOylation has been studied in holometabolous species, particularly in the dipteran Drosophila melanogaster, which contains a single SUMO gene (smt3). This has led to the assumption that insects contain a single SUMO gene. However, the analysis of insect genomes shows that basal insects contain two SUMO genes, orthologous to vertebrate SUMO1 and SUMO2/3. Our phylogenetical analysis reveals that the SUMO gene has been duplicated giving rise to SUMO1 and SUMO2/3 families early in Metazoan evolution, and that later in insect evolution the SUMO1 gene has been lost after the Hymenoptera divergence. To explore the consequences of this loss, we have examined the characteristics and different biological functions of the two SUMO genes (SUMO1 and SUMO3) in the hemimetabolous cockroach Blattella germanica and compared them with those of Drosophila Smt3. Here, we show that the metamorphic role of the SUMO genes is evolutionary conserved in insects, although there has been a regulatory switch from SUMO1 in basal insects to SUMO3 in more derived ones. We also show that, unlike vertebrates, insect SUMO3 proteins cannot form polySUMO chains due to the loss of critical lysine residues within the N-terminal part of the protein. Furthermore, the formation of polySUMO chains by expression of ectopic human SUMO3 has a deleterious effect in Drosophila. These findings contribute to the understanding of the functional consequences of the evolution of SUMO genes.
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PMID:Evolution of SUMO Function and Chain Formation in Insects. 2653 42

The ubiquitin-like modifier (UBL) SUMO (Small Ubiquitin-Like Modifier) regulates protein function. Structural rather than sequence homology typifies UBL families. However, individual UBL types, such as SUMO, show remarkable sequence conservation. Selection pressure also operates at the SUMO gene copy number, as increased SUMO levels activate immunity and alter flowering time in Arabidopsis. We show how, despite this selection pressure, the SUMO family has diversified into eight paralogues in Arabidopsis. Relationships between the paralogues were investigated using genome collinearity and gene tree analysis. We show that palaeopolyploidy followed by tandem duplications allowed expansion and then diversification of the SUMO genes. For example, Arabidopsis SUMO5 evolved from the pan-eudicot palaeohexaploidy event (gamma), which yielded three SUMO copies. Two gamma copies were preserved as archetype SUMOs, suggesting subfunctionalization, whereas the third copy served as a hotspot for SUMO diversification. The Brassicaceae-specific alpha duplication then caused the duplication of one archetype gamma copy, which, by subfunctionalization, allowed the retention of both SUMO1 and SUMO2. The other archetype gamma copy was simultaneously pseudogenized (SUMO4/6). A tandem duplication of SUMO2 subsequently yielded SUMO3 in the Brassicaceae crown group. SUMO3 potentially neofunctionalized in Arabidopsis, but it is lost in many Brassicaceae. Our advanced methodology allows the study of the birth and fixation of other paralogues in plants.
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PMID:Whole-genome duplications followed by tandem duplications drive diversification of the protein modifier SUMO in Angiosperms. 2693 36