Speaker
Description
Pathogenic bacteria have evolved numerous virulence factors to overcome host defense mechanisms. Among the most effective are secreted proteolytic enzymes (proteases) that specifically target and inactivate key proteins of the human immune system, critically including protective mucosal antibodies such as Immunoglobulin A (IgA), at the host-pathogen interface. This represents a vital immune evasion strategy, facilitating bacterial colonization and infection. The high substrate specificity of these IgA-cleaving proteases suggests a sophisticated, exosite-driven molecular recognition mechanism that is currently not well understood.
Our project aims to address this knowledge gap by establishing an integrative structural biology pipeline to elucidate the molecular basis of this IgA-cleavage activity. We are utilizing single-particle cryo-electron microscopy (cryo-EM) at the ALBA-hosted JEMCA facility to determine the high-resolution, three-dimensional structure of the enzyme, both in its free state and in complex with its large antibody substrate. To complement these studies and capture the full conformational landscape, we plan to leverage ALBA's macromolecular crystallography (MX) beamlines, XALOC and XAIRA, for high-resolution analysis of the enzyme's rigid domains and to facilitate future high-throughput inhibitor screening.
This multimodal approach will provide comprehensive atomic-level insight into the enzyme's architecture and the dynamic enzyme-substrate interplay. Ultimately, our research will establish an atomic framework for understanding this fundamental host-pathogen interaction and provide the foundation for the rational design of therapeutic inhibitors. Furthermore, our findings will set the stage for the development of these enzymes as precision tools in proteomics-based disease monitoring, and potentially, even as a targeted treatment for IgA nephropathy.