We have identified a new Plasmodium falciparum erythrocyte binding protein that appears to be located in the micronemes of the merozoite stage of the parasite and membrane linked through a glycosylphosphatidylinositol (GPI) anchor. The protein is designated GPI-anchored micronemal antigen (GAMA) and was identified by applying a set of selection criteria to identify previously uncharacterized merozoite proteins that may have a role in cell invasion. The protein is also present in the proteomes of the sporozoite and ookinete micronemes and is conserved throughout the genus. GAMA contains a novel domain that may be constrained by disulfide bonds and a predicted C-terminal hydrophobic sequence that is presumably replaced by the GPI. The protein is synthesized late during schizogony, processed into two fragments that are linked by a disulfide bond, and translocated to an apical location, which is probably the micronemes. In a proportion of free merozoites GAMA can also be detected on the parasite surface. Following erythrocyte invasion the bulk of the protein is shed in a soluble form, although a short C-terminal fragment may be carried into the newly invaded red blood cell. The protein was shown to bind reversibly to erythrocytes and therefore represents a new example of a host cell binding protein.Malaria is a potentially fatal disease that still devastates poverty-stricken nations more than a century after the protozoan parasite Plasmodium was identified as its causative agent. An accurate estimation of mortality remains elusive, although recent estimates suggest that just over 2.5 billion people live at risk of infection by Plasmodium falciparum (22), the species of the parasite responsible for the vast majority of deaths. It is believed that there are in the range of 500 million clinical episodes of P. falciparum infection each year, with the vast majority of the estimated 1 million fatalities occurring in children under the age of 5 years in sub-Saharan Africa (50). The often-fruitless efforts to develop a licensed malaria vaccine, along with the emergence of drug-resistant parasites and insecticide-resistant mosquitoes, highlight the urgency with which new points of attack to combat malaria need to be identified. The arrival of the P. falciparum genome sequence (15), along with its transcription (8, 34) and proteomic (14, 33) profiles, has provided great opportunities to identify novel drug and vaccine candidates.The asexual blood stage of the parasite is exclusively responsible for the clinical symptoms of malaria, and so, understandably, great efforts have gone into elucidating the molecular mechanism of erythrocyte invasion that is driven by the parasite's actomyosin motor. Although this process remains largely undefined, it is known that the secretory organelles located at the apical end of the invasive merozoite are pivotal. These organelles consist minimally of micronemes, rhoptries, and dense granules. Proteins belonging to the Duffy binding-like erythrocyte binding protein (18,37,49) and P. falciparum ...

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