Clusters of malaria parasites growing inside human red blood cells.

Mike Blackman : Proteolytic processing and function of apical membrane antigen-1 (AMA1)

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AMA1 is a large integral membrane protein that is secreted from micronemes, a set of specialised apically-located secretory organelles, onto the surface of the merozoite just prior to invasion. There AMA1 plays a critical role in invasion and is eventually shed by the action of PfSUB2 (Harris et al., 2005).

AMA1 is of particular interest because antibodies against it can prevent host cell invasion by the parasite. We wish to determine the function of AMA1 and the role of its shedding, as well as defining functionally important regions of the protein that might form part of a sub-unit malaria vaccine (Pizarro et al., 2005). To this end, we have mapped the epitope for one of the most efficient monoclonal antibodies which inhibit invasion (Collins et al., 2007), and shown that this may function by interfering with interactions between AMA1 and partner proteins involved in formation of the moving junction, a transient doughnut-like structure through which the invading merozoite moves as it invades an erythrocyte (Collins et al., 2009). Proteolytic shedding of AMA1 by the subtilisin-like protease SUB2 plays an important role in invasion and evasion of antibodies (Olivieri et al., 2011).

X-ray crystal structure of the AMA1 ectodomain

Figure 1: X-ray crystal structure of the AMA1 ectodomain (Click to view larger image) The X-ray crystal structure of the AMA1 ectodomain has shown that it comprises three disulphide-constrained domains. Two of these belong to the PAN module superfamily, implicated in protein-protein or protein-carbohydrate interactions. Here, domains I (yellow), II (blue) and III (green) are shown in three orientations.