Mechanism of protein translocation across the parasitophorous vacuole membrane of the malaria parasite

Malaria has caused widespread death tolls around the globe. According to the World Malaria Report released in November 2018, the number of malaria cases in 2017 spanned 90 countries and totaled 219 million worldwide. After infecting the human host, the malaria parasite remodels the cell by exporting hundreds of effector proteins that travel from the endoplasmic reticulum to the parasitophorous vacuole (PV). Upon arrival, these proteins are unfolded and cross the PV membrane with the aid of the Plasmodium translocon of exported proteins (PTEX), a membrane protein complex. Despite the progress in understanding the general protein export process, the molecular mechanism and dynamics of protein translocation across PTEX remain poorly understood. Recent crystal structures of the PTEX engaged and resetting states provide useful starting points for simulating and uncovering the translocation mechanism. By combining structural information with molecular dynamics (MD) simulations, I aim to uncover the PTEX translocation mechanism in detail. Coarse-grained MD simulations will allow me to simulate the translocation process (including pre-translocation and post-translocation). I will also calculate the free-energy landscape from MD snapshots to identify distinct states and their associated timescales in the translocation processive phase. In turn, this can inform the design of inhibitors that target PTEX and other related parasitic translocons.

Enabling Technologies & Assays

Aug 2020 — Sep 2021

$43,549

Canada