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  • Vincent Luca

    Vincent Luca

    Postdoctoral Research fellow, Molecular and Cellular Physiology

    Bio My research in the Garcia Lab is focused on understanding the molecular basis for Notch receptor-ligand interactions, a critical signaling event for mammalian cell fate determination and the pathogenesis of many cancers. Until recently, we had not been able to ?see? how Notch receptors engage ligands Delta-like and Jagged because their nearly undetectable binding affinity prevents reconstitution of stable complexes for structural studies. To overcome this obstacle, we used in vitro evolution to engineer mutations in Delta-like 4 (DLL4) that enhanced affinity for Notch1 and facilitated co-crystallization of the complex. The Notch1-DLL4 structure revealed an antiparallel, two-site binding interface in which O-linked glycan modifications of Notch1 residues make specific and essential contacts with DLL4. Changes in Notch glycosylation state are known to bias recognition towards certain ligands, and the Notch1-DLL4 structure thus rationalizes a mechanism for glycan-mediated tuning of Notch-ligand selectivity. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways

    Gaining structural access to the Notch-ligand interface was a critical first step toward improved therapeutic targeting of the pathway. With this structural information to guide us, we will now be able to design novel ligands with enhanced selectivity and affinity for a number of immunologically focused applications. For example, we are generating (1) receptor-specific ligands that inhibit tumor growth while minimizing off-target toxicity, (2) stromal cell lines that express high-affinity ligands to enhance T-cell maturation in vitro, and (3) bi-specific ligands that activate Notch on desired cell types. In the future, we hope to create a diverse ?toolbox? of engineered ligands for use as diagnostics and therapeutics in a variety of contexts.

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