Interconnected ganglia

This project is now closed

Functional analysis of SERA6, a cysteine protease of the malarial parasitophorous vacuole

Project supervisor: Mike Blackman (Parasitology)

The most severe form of clinical malaria results from asexual replication of the protozoan parasite Plasmodium falciparum within a membrane-bound parasitophorous vacuole (PV) in circulating red blood cells. At periodic intervals, the bounding PV and red cell membranes rupture in a parasite-driven process called egress, allowing dissemination of daughter merozoites. Egress is sensitive to selective inhibitors of proteases, but little is known about the effector enzymes involved or how their activity is regulated. Parasite enzymes required for egress are potential targets for new antimalarial drugs.

Our previous work (Yeoh et al, 2007; Blackman, 2008; de Monerri et al, 2011) has shown that egress is temporally preceded by the discharge into the PV of a parasite serine protease called PfSUB1. In the PV, PfSUB1 mediates the precise proteolytic processing of several parasite proteins, including a papain-like protein called SERA6. Since many proteases are activated by proteolysis, we have hypothesised (Blackman, 2008) that processing by PfSUB1 may convert SERA6 into a proteolytically active product that plays a role in egress. Recent work (Ruecker et al, 2012) supports this, showing that the canonical catalytic Cys residue of SERA6 is essential for parasite viability, that processing of SERA6 by PfSUB1 is also required for parasite survival, and that a SERA6 orthologue possesses cysteine protease activity which is activated by PfSUB1 cleavage in vitro.

This PhD project aims to build on that work to obtain a detailed picture of the importance and function of SERA6. Genetic modification of P. falciparum will be used to study the consequences of gene knockout or over-expression of SERA6, using an episomal complementation approach. In parallel, recombinant expression of SERA6 combined with mass spectrometry will be used to determine the substrate specificity of the enzyme and the repertoire of physiological substrates of SERA6. The results will shed light on the role of SERA6 in a critical step in the life cycle of a major human pathogen.

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