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CURRENT RESEARCH The SUMO-1 protein modification pathway SUMO-1 is a small ubiquitin-like protein. SUMO-1 can be covalently conjugated to other proteins through an isopeptide linkage in a manner similar to ubiquitin. The SUMO-1 conjugation pathway utilizes enzymes that both show sequence similarity to enzymes in the ubiquitin pathway and utilize similar biochemical mechanisms. A large and growing number of SUMO-1 conjugation substrates have been reported in vertebrates to date. Notably, the profile of SUMO-1 conjugated changes substantially in response to altered cellular conditions, suggesting that there are mechanisms to control the specificity of conjugation and/or deconjugation of SUMO-1 differentially between distinct substrates. RanGAP1 was the first documented substrate for conjugation with SUMO-1. However, the functional significance of this conjugation has not been fully clarified. We have been particularly interested in understanding the role or SUMO-1 in regulating RanGAP1, both because of our interest in the Ran pathway and because we believe that understanding this interaction will serve as a paradigm for other SUMO-1 conjugation targets. We have recently found that SUMO-1 conjugation is required for mitotic localization of RanGAP1. Our findings suggests that a major role of SUMO-1 conjugation to RanGAP1 may be the spatial regulation of the Ran pathway during mitosis. Together, these results imply that Ran-GTP gradients may be regulated in mitosis in a manner that is significantly more complex than previously anticipated. In order to study the SUMO-1 pathway more generally, we have also been examining the enzymes responsible for its conjugation to and deconjugation from other cellular proteins. We are currently undertaking a strategy to directly disrupt these proteins and examine the consequences for the Ran pathway and other cellular functions.  Figure 2: The SUMO-1 conjugation pathway. SUMO-1 is initially proteolytically processed by C-terminal hydrolases to its active form. It then serves as the substrate in the ATP-dependent formation of an isopeptide bond between the free carboxyl group of the C-terminal glycine in SUMO and the e-amino group of a lysine in the acceptor protein. This reaction is mediated by Aos1/Uba2 (E1 enzyme) and Ubc9 (E2 enzyme). E3 ligases have recently been described for this system, but little is known regarding their mechanism and function. Cleavage of the isopeptide bond is mediated by isopeptidases. |
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Section on Cell Cycle Regulation |
