Designer Proteins for Cell Signaling
Abstract:
Over the years, I worked on designing ‘brand new’ (de novo) protein complexes—ordered and disordered—using computational tools such as Rosetta. I created large symmetric protein assemblies through the rigid helical fusion of smaller protein chains and later expanded this approach to design disordered system-wide protein networks with unique mechano-fluidic properties inside and outside of cells. Using these de novo protein complexes, I developed a soluble agonist for Notch signaling, a key pathway in cell development and immune function.

Designing a ‘cytokine-like’ soluble Notch agonist has been a long-standing challenge because Notch signaling typically requires direct cell-cell contact and mechanical pulling. After successfully designing this agonist, I uncovered its mechanism of action and applied it in T cell development from hematopoietic stem cells in a bioreactor, advancing cell-based therapies. The agonist also boosted T cell function in vivo by expanding antigen-specific T cells during vaccination and promoting antibody class switching, demonstrating significant promise as an immunotherapy.

In my future lab, I will use computational tools to design complex heteromeric protein assemblies rarely found in nature. I aim to explore their vast potential in controlling cellular signaling, particularly in immune and stem cells, to develop innovative therapies.