Illuminating Notch receptor-ligand selectivity through structure-guided protein engineering

H. Lee Moffitt Cancer Ctr & Res Inst, Tampa FL

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Abstract

PROJECT SUMMARY Overall vision of the research program. My lab uses structure-guided engineering to reprogram receptor signaling for biomedical applications. By exploring the structural biology of cell surface receptors, our goal is to uncover novel strategies for engineering customizable signaling outputs. My research program largely focuses on receptor families that influence the development or maturation of stem cells. The Notch signaling pathway controls several aspects of stem cell and immune cell development, and my team has spent several years illuminating the structural biology of Notch signaling complexes. Additionally, we are developing several tools to turn Notch signaling “on” or “off” in desired tissues. We have also expanded our structural studies to include proteins that mediate crosstalk between developmental signaling pathways and complexes between emerging immune inhibitory receptors and their ligands. Overview of research in the laboratory. Our current research is focused on two major areas. The first is the development of biotechnological toolkits that can fine-tune receptor signaling depending on cellular context. Using the Notch pathway as a model system, we are establishing design principles for tissue-specific activators or inhibitors of receptor signaling. For the second area, we are studying the molecular basis for crosstalk between developmental signaling pathways. We have identified multiple non-canonical ligands of Notch and TGF-β family receptors that regulate signaling through both pathways. Our structure-function studies of these complex regulatory networks will expand our understanding of developmental signaling and illuminate new opportunities for therapeutic intervention. Goals for the next five years. Our goals are to: (i) assess the ability of Notch-modulating biologics to influence immune and stem cell biology in various biological systems; (ii) elucidate the molecular mechanisms by which non-canonical Notch ligands regulate developmental signaling; and (iii) identify novel extracellular Notch binding partners and determine their effect on Notch signaling activity. These research areas will provide a strong foundation for our continued research in developmental signaling, which will enable us to engineer novel biotechnologies for regenerative medicine and therapeutic development.