Interrogating host-parasite interactomes with multiscale proteomics

Parasites are a major cause of human and livestock disease. Malaria alone causes at least half a million deaths per year, and together these single-celled pathogens cause billions of dollars of economic damage through medical burden and food insecurity. Parasites owe their remarkable infectious ability to highly-adapted proteomes. Their adaptation allows them to remodel the host’s cells to proliferate and out-wit host immunity. The parasite proteins exploit the already vulnerable host proteome by re-wiring its subcellular programs through protein-protein interactions (PPI) and post-translational regulation of host proteins. Interrupting the complex set of host-parasite interactions presents a strategy for designing new therapeutics, but our abilities are limited by the lack of structural data which follow these dynamic processes at a system-wide level. This will help us understand the molecular details of each stage as well as the transitions between them. To understand these interactions in further detail, focusing on the PTEX complex and the parasite proteins that interact with the ankyrin complex, we will employ hydrogen-deuterium exchange mass-spectrometry (HDX-MS). HDX-MS will aid us in understanding the binding sites of the parasite proteins, as well as the conformational ensembles of the resultant host-parasite protein complexes. This data will be complemented by employing systems-wide structural proteomics across the remodeling stages. Combining all these data with computational simulations will provide a new understanding of plasmodium remodeling of infected erythrocytes.

Project details

Basic Science

Apr 2024 — Mar 2029

$1.68M

United Kingdom