CAREER: Assembly Mechanisms of Supramolecular Signaling Platforms

Johns Hopkins University, Baltimore MD

Investigators

Abstract

The numerous reactions that support life must be highly coordinated in the cell to optimize the use of resources and respond to environmental cues. Isolation of competing processes into distinct sub-cellular organelles minimizes some potential intracellular conflicts. However, not all sub-cellular organizational units classify as organelles, as they lack a membrane barrier that would define them as such. A newly appreciated organizational unit in the cell is a signaling "hub." Construction of the hub from the ordered assembly of protein building blocks can be triggered by diverse molecular events. This hub, or platform, then recruits additional molecules that initiate the cell's response to the triggers by activating and releasing a downstream signal. The hub both amplifies distress signals and allows for a coordinated response to simultaneous events or insults. This project aims to establish a framework for understanding how these signal platforms assemble and operate at the molecular level. This information is fundamental to understanding the coordination of the complex network of cellular processes. The PI directs the Biophysics Research for Baltimore Teens (BRBT) program, an outreach program for which exposes Baltimore city high school students to current research areas. Specifically, this project will investigate how supramolecular assemblies mediate stress-response pathways that lead to cell death. The research strategy includes computational methods such as Rosetta and Monte Carlo simulations, Cryo-Electron Microscopy, and quantitative measurements in both cell-free and cell-based systems. The first goal is to determine how different upstream receptors preferentially homo-polymerize, avoid crosstalk, yet recognize a single adaptor assembly. The second goal is to elucidate how different regulators target and inhibit specific signaling components in these pathways. The outcome here will delineate structural and biochemical mechanisms by which supramolecular assemblies coordinate signal integration at different stages of the cell-death pathway. 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.