Assembly and Regulation Mechanisms of Filamentous Signaling Platforms

About This Grant

The numerous molecular interactions that support life must be highly regulated in the cell to achieve selectivity and precision. A newly identified method with which cells achieve this is via the sequential assembly of filamentous signaling platforms which are composed of a specific class of proteins. These large, supramolecular structures adopt distinct architectures, and shape complementarity plays a key role in recognizing their specific partners. Their assembly provokes a “signal” which triggers a cellular response. The filamentous signaling hubs can condense into large organelle-like entities, which can be vital for preventing any crosstalk with unrelated signaling pathways. This project aims to investigate how filamentous signaling 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 in which high school students from Baltimore and the surrounding areas can be part of current research efforts. Specifically, this project will investigate how filamentous signaling platforms execute a cell-death pathway. The research strategy includes computational methods such as Rosetta, Electron Microscopy, single-molecule force measurements, and quantitative assays in both cell-free and cell-based systems. The first goal is to determine how architectural complementary dictates the interacting partners within a specific group of signaling filaments. The second goal is to investigate the mechanical forces involved in assembling such filamentous structures on DNA. The third goal is to elucidate how different regulators target and inhibit specific signaling components in these pathways. The outcome here will delineate structural, biochemical, physical mechanisms by which filamentous assemblies preserve the signaling specificity 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.