The small ubiquitin-related modifier SUMO is a highly conserved member of the ubiquitin/ubiquitin-like protein family involved in post-translational modification of target proteins. The importance of the SUMOylation pathway is underscored by its involvement in all developmental stages in multicellular organisms. Unlike ubiquitin, which generally targets substrates for degradation by the 26S proteasome, SUMO does not target proteins for degradation, but is known to be involved in several pathways including signal transduction, transcription, chromatin remodeling, DMA repair, mitosis, viral infection, and nucleocytoplasmic trafficking. Several tumor suppressors such as the promyelocytic leukemia protein (PML) and p53 are SUMO modified as part of their normal regulation. Nonetheless, the mechanisms underlying its regulation still remain unclear. Using a multi-faceted approach, employing x-ray crystallography, yeast genetics and biochemical analysis, I intend to structurally and functionally characterize SUMO in complex with the E1 and E2 enzymes of the SUMO conjugation pathway. This structure, along with biochemical analysis, will provide a model for SUMO activation and transfer to an E2, advancing our current understanding of the molecular mechanisms underlying SUMO activation, as well as activation of other ubiquitin/ubiquitin-like proteins. This study, combined with previous structural studies, will offer a unique opportunity to understand the molecular recognition of SUMO, providing a basis to redesign a SUMO molecule with the ability to be precisely modulated by components of the pathway. ? ?
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| Lu, Xuequan; Olsen, Shaun K; Capili, Allan D et al. (2010) Designed semisynthetic protein inhibitors of Ub/Ubl E1 activating enzymes. J Am Chem Soc 132:1748-9 |
| Mohideen, Firaz; Capili, Allan D; Bilimoria, Parizad M et al. (2009) A molecular basis for phosphorylation-dependent SUMO conjugation by the E2 UBC9. Nat Struct Mol Biol 16:945-52 |
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| Capili, Allan D; Lima, Christopher D (2007) Structure and analysis of a complex between SUMO and Ubc9 illustrates features of a conserved E2-Ubl interaction. J Mol Biol 369:608-18 |
