Elucidating the biophysical mechanisms of transbilayer coupling by protein condensates

University Of Texas At Austin, Austin TX

Investigators

Abstract

This project investigates a previously unknown mechanism by which proteins come together on the surfaces of cells to transmit information from the outside world, which could ultimately be harnessed to communicate with cells and tissues. Like fences and walls, cells use lipid membrane to protect themselves and divide their contents into functional compartments. While this compartmentalization is useful to cells, it also requires cells to develop ways of communicating across membrane boundaries. This project investigates a new means of communication through membranes in which a liquid-like droplet of protein on one side of the membrane locally rearranges lipids to send a signal to a droplet of protein on the opposite side of the membrane. By explaining the mechanism behind this newly discovered form of communication, this research provides a better understanding of how cells communicate with the outside world and with one another. Ultimately, this understanding has the potential to inspire new ways of controlling cellular behavior to meet biomedical needs. In parallel, the investigators are conducting a multi-level outreach program involving local schools, teachers, undergraduates, and graduate students. To inspire the next generation of biophysicists, this program partners with participants to create new hands-on experiments for K-12 students. Liquid-like protein condensates organize diverse cellular functions. Though originally discovered in the cytosol and nucleoplasm, many condensates function on membrane surfaces. This work is inspired by the recent discovery that condensates on one side of a suspended planar membrane colocalize spontaneously with those on the other side, resulting in transbilayer coupling. These findings suggest a new means of transbilayer communication. This project aims to identify the fundamental mechanisms responsible for transbilayer coupling of protein condensates. The research involves quantitative biophysics experiments, guided by molecular-level simulations. Further, as a physiological example of condensate coupling, transbilayer interactions between glycosphingolipids and actin are being investigated. In particular, the role of coupling between condensates consisting of extracellular Galectin proteins and intracellular condensates consisting of actin-interacting proteins is being evaluated. These studies are providing novel biophysical insights and experimentally validated simulation tools for understanding and predicting the impact of protein condensates on membrane surfaces throughout the cell. Specifically, this work has the potential for a transformative impact on biophysical understanding of cell biology by elucidating the molecular-scale mechanisms behind a previously unknown mechanism for transbilayer communication and evaluating the role of this mechanism in the cellular process of glycosphingolipid traffic. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.