Signal transduction pathways rely on reversible chemical modifications to relay information within and across cells. Covalent modification of protein substrates by ubiquitin and the ubiquitin-like proteins such as SUMO (small ubiquitin-like modifier) contribute to pathways that regulate cellular functions including nuclear transport, cytokinesis, chromosome segregation, G2-M cell cycle progression and transcriptional regulation among many others. Post-translational modification by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins requires the sequential action of E1 activating enzymes, E2 conjugating enzymes and E3 ligases while Ub/Ubl processing and deconjugation is catalyzed by Ub/Ubl-specific proteases. Ubiquitin and SUMO conjugation play an integral role in eukaryotic nuclear metabolism and cell cycle control and our studies are of direct relevance to human health, cancer, and the mission of the NIH. This proposal seeks to address the functional significance for components of the ubiquitin and SUMO conjugation pathways through structural, biochemical and genetic studies that will establish the basis for Ub/Ubl 1) activation, 2) conjugation by E2 and E3 enzymes, 3) signal transduction through characterization receptors that recognize Ub/Ubl-conjugated substrates. The enzymes, mechanisms and factors that constitute ubiquitin and SUMO protein conjugation pathways are conserved so our studies will be broadly relevant and will impact research in other Ub/Ubl-related pathways.
Post-translational protein modification relays information within and across cells in signal transduction pathways that control the activities of protein substrates as well as their spatial and temporal distribution. Covalent modification of proteins by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as SUMO (small ubiquitin-like modifier) and Nedd8 impact nearly all facets of cellular metabolism including cell cycle control, protein degradation, protein localization, nuclear transport, cytokinesis, chromosome segregation, and transcriptional regulation among many others. This proposal seeks to explore the mechanisms that underlie protein modification by ubiquitin and SUMO through structural, biochemical and genetic studies that will address 1) Ub/Ubl activation by the E1 enzyme, 2) SUMO conjugation by E2 and E3 enzymes, 3) structural analysis of PCNA, its modification by Ub/Ubl proteins, and its recognition by Srs2 and Eco1. The ubiquitin and SUMO pathways regulate many processes that are associated with human disease conditions including neurodegenerative disorders, cancer, and inflammation.
| Lau, Yue-Ting K; Baytshtok, Vladimir; Howard, Tessa A et al. (2018) Discovery and engineering of enhanced SUMO protease enzymes. J Biol Chem 293:13224-13233 |
| Cappadocia, Laurent; Lima, Christopher D (2018) Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism. Chem Rev 118:889-918 |
| Streich Jr, Frederick C; Lima, Christopher D (2016) Capturing a substrate in an activated RING E3/E2-SUMO complex. Nature 536:304-8 |
| Békés, Miklós; van der Heden van Noort, Gerbrand J; Ekkebus, Reggy et al. (2016) Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease. Mol Cell 62:572-85 |
| Cappadocia, Laurent; Pichler, Andrea; Lima, Christopher D (2015) Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase. Nat Struct Mol Biol 22:968-75 |
| Békés, Miklós; Rut, Wioletta; Kasperkiewicz, Paulina et al. (2015) SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme. Biochem J 468:215-26 |
| Streich Jr, Frederick C; Lima, Christopher D (2014) Structural and functional insights to ubiquitin-like protein conjugation. Annu Rev Biophys 43:357-79 |
| O'Rourke, Jacqueline Gire; Gareau, Jaclyn R; Ochaba, Joseph et al. (2013) SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 4:362-75 |
| Olsen, Shaun K; Lima, Christopher D (2013) Structure of a ubiquitin E1-E2 complex: insights to E1-E2 thioester transfer. Mol Cell 49:884-96 |
| Lima, Christopher D; Schulman, Brenda A (2012) Structural biology: A protein engagement RING. Nature 489:43-4 |
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