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Proteolysis Putative SUMO-1 pathway

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Proteolysis Putative SUMO-1 pathway

Putative SUMO-1 pathway

Sumoylation is a multi-step protein modification reaction. It implicates Smallubiquitin-like modifier (SUMO) proteins, such as SMT3 suppressor of mif two 3 homolog 1 (SUMO-1 ). These proteins get attached covalently to lysine residues ofsubstrate/target proteins. As a result, in contrast to ubiquitination that targetsproteins for degradation, activities of the sumoylated proteins get modulated to affect anumber of biological functions, including control of gene expression, maintenance ofgenome integrity, intracellular transport and protein stability [1], [2].

Attachment of SUMO-1 to substrate proteins is carried out by enzymatic cascadeinvolving SUMO-activating enzyme (E1), SUMO-conjugating enzyme (E2) and SUMO proteinligase (E3). A group of proteases known as SENPs are involved in both the maturation ofSUMO precursors (endopeptidase cleavage) and deconjugation of the targets (isopeptidasecleavage).

SUMO-1 is processed by SUMO1/sentrin specific peptidase 1 ( SENP1 )(endopeptidase cleavage) before being activated. Processed SUMO-1, in theATP-dependent manner, is covalently linked to the SUMO E1-activating enzyme complex (SAE1/2 ) composed of two catalytically active subunits, SUMO1 activating enzymesubunit 1 ( SAE1 ) and Ubiquitin-like modifier activating enzyme 2 ( SAE2). SUMO-1 is then transferred to the SUMO E2-conjugating enzymes, such asUbiquitin-conjugating enzyme E2I ( E2I ) and Ubiquitin-conjugating enzyme E2E 3 (UBE2E3 ), that mediate target protein modification by SUMO E3 ligases, such as RANbinding protein 2 ( RanBP2 ), Chromobox homolog 4 ( Pc2 ) and specificE3-like ligases PIAS1 and PIAS2 ( Protein inhibitors of activated STAT, 1and 2) [3], [4], [5], [6], [1]. Cleavage of the SUMO-1 from the target protein is mediated bySENP1 peptidase (isopeptidase cleavage) [1].

Mdm2 p53 binding protein homolog ( MDM2 ) is an ubiquitin ligase (E3) that actson Tumor protein p53 ( p53 ). It attaches Ubiquitin to p53 leadingto proteasomal degradation of the latter [7]. E3 ligase RanBP2 is anuclear pore protein and E3 ligases PIAS1 and PIAS2 are localized withinthe nucleus. MDM2 is sumoylated during nuclear translocation by RanBP2,and then sumoylated again in the nucleus by PIAS1 and PIAS2 [8].

PIAS1 and PIAS2 also promote sumoylation of several transcriptionfactors, such as p53, c-Jun and SP3. This modification modulatestheir transcriptional activity, e.g., SUMO-1 modification silences SP3activity [4], [9].

Sumoylation is involved in both the direct regulation of p53 protein stabilityand function via direct modification of p53, and indirect modulation of thestability of MDM2. Although, the functional consequence of direct SUMO-1modification of p53 is under debate, it is generally believed that sumoylationrepresses activity of this transcription factor. The indirect process has to do with, theturnover rate of p53 being related to E3 ubiquitin ligase activity of MDM2, the latter itself being a target of sumoylation. SUMO-1 -modified MDM2cannot be ubiquitinated as efficiently as the free MDM2. Thereby, SUMO-1-modified MDM2 exhibits reduced self-ubiquitination which leads to an accumulationof MDM2. Since p53 is a target of MDM2 E3 ubiquitin ligaseactivity, the p53 levels stay low in the presence of SUMO-1 -modifiedMDM2 [4], [6].

RanBP2 promotes sumoylation of Ran GTPase activating protein 1 ( RanGAP1), stimulates RanGAP1 functions and increases the accumulation of properly foldedRanGAP1 protein [10], [11], [12].

Activation of Nuclear factor NF-kappa-B ( NF-kB ) is achieved by ubiquitinationand proteasome-mediated degradation of inhibitory I-kappa-B proteins ( NFKBIA orNFKBIB). The latter inactivate NF-kB by trapping it in the cytoplasm.NFKBIA, conjugated to SUMO-1, is resistant to ubiquitin-induceddegradation. Thus, NFKBIA sumoylation inhibits signal-induced activation ofNF-kB -dependent transcription [13].

The sumoylation of TNF receptor superfamily member 6 ( FasR(CD95) ), v-Mybmyeloblastosis viral oncogene homolog ( c-Myb ), Promyelocytic leukemia protein (PML ), Heat shock transcription factor 1 ( HSF1 ), Heat shock transcriptionfactor 2 ( HSF2 ), Glucocorticoid receptor ( GCR-alpha ), Nuclear antigenSP100 ( SP100 ), Death-domain associated protein ( DAXX ), and DNAtopoisomerase II ( TOP2 ) regulates subcellular localization, stability andfunctional activity of these proteins [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30].