MRC National Institute for Medical Research, London
Science for Health
Mike Blackman group project:
Subtilisin-like proteases of the malaria merozoite
Proteases are known to play important roles during the life cycle of the malaria parasite. We are working on a family of P. falciparum subtilisin-like serine proteases (subtilases) that are involved in red blood cell invasion and exit.
Molecular model of the PfSUB1 catalytic domain
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The predicted catalytic serine, histidine and aspartic acid residues (black) are shown in ball-and-stick representation
PfSUB1 was the first malarial subtilase to be identified (Blackman et al., 1998). It is highly conserved across the genus and appears to play a critical role in the blood-stage life cycle. We recently showed that PfSUB1 has a central regulatory role in release of the parasites from the host cell. PfSUB1 is discharged from merozoite organelles known as exonemes into the parasitophorous vacuole space, where it is responsible for processing a family of papain-like proteins known as SERA, triggering a cascade of proteolytic events which culminate in host cell rupture (Yeoh et al., 2007). PfSUB1 is also involved in remodelling of several essential merozoite surface proteins in preparation for invasion of a new cell. Current investigations of PfSUB1 are focused on determining its structure, dissecting the timing and significance of these proteolytic events, and identifying further substrates.
PfSUB1: a malaria merozoite serine protease
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Surface representation of the PfSUB1 molecular model, showing the substrate binding cleft with a 10 amino acid peptide substrate, derived from the physiological substrate SERA5, bound.
PfSUB2 (Hackett et al., 1999) is a large membrane-bound subtilase which, like PfSUB1, is expressed in blood-stage merozoites and is found in all Plasmodium species. PfSUB2 is the prime candidate for the ‘sheddase’ which clips important surface proteins such as MSP1 and AMA1 from the surface of the merozoite during erythrocyte invasion (Harris et al., 2005). We are actively pursuing the function of this protease, using biochemical approaches and genetic modification of P. falciparum.
Activity of PfSUB2
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On the left is an immunofluorescence image showing the surface location of AMA1 (green) on released P. falciparum merozoites. On the right is a schematic depicting proteolytic shedding of AMA1 and another merozoite surface protein complex called MSP1. The protease PfSUB2 mediates release of both proteins by cleaving them at sites close to the membrane.
Blackman group
Recent publications
Research projects
- Proteolytic processing and function of apical membrane antigen-1 (AMA1)
- Subtilisin-like proteases of the malaria merozoite
- Rhomboid-like proteases in red blood cell invasion
Blackman biography
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