Faculty Affairs and Academic Programs
Vu Nguyen
Life Sciences; Agriculture and Veterinary Sciences
Establishing Motion as a Programmable Property of Protein Function
Proteins must navigate crowded cellular environments to function, yet we do not understand how motion is regulated in vivo. Most proteins in the cell nucleus contain intrinsically disordered regions (IDRs)—flexible segments that mediate dynamic organization of biomolecular condensates. Unlike folded domains whose structures reveal their function, IDRs remain intractable to rational engineering. I hypothesize that IDRs serve as "navigation modules" that encode motion instructions, enabling proteins to efficiently traverse and organize in nuclear space. This project explores intranuclear motion as a tunable protein property. Using advanced single-molecule tracking microscopy, we have developed a ‘motion-mapping’ platform to illuminate IDRs’ role in regulating protein dynamics in living cells. Preliminary experiments demonstrate that charge patterning in IDRs dramatically influences diffusion rates and compartmentalization, validating that IDRs encode motion in their amino acid composition. We will systematically decode the relationship between IDR sequence features and motion behaviors. By testing natural IDR variants with diverse compositional properties and correlating their dynamics with sequence characteristics, we will establish quantitative rules linking amino acid composition to intracellular motion. Success would enable rational design of proteins with desired dynamic properties, enabling applications spanning from understanding disease mechanisms—such as nuclear dysfunction in cancer or aberrant protein aggregation in neurodegeneration—to engineering synthetic proteins with programmable localization and activity.
