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J. Biol. Chem., Vol. 281, Issue 8, 5197-5208, February 24, 2006

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A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites^*

Jake Baum¹², Dave Richard²³, Julie Healer, Melanie Rug, Zita Krnajski, Tim-Wolf Gilberger, Judith L. Green^¶, Anthony A. Holder^¶, and Alan F. Cowman⁴

From the Division of Infection and Immunity, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany, and the ^¶National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, United Kingdom

Apicomplexan parasites constitute one of the most significant groups of pathogens infecting humans and animals. The liver stage sporozoites of Plasmodium spp. and tachyzoites of Toxoplasma gondii, the causative agents of malaria and toxoplasmosis, respectively, use a unique mode of locomotion termed gliding motility to invade host cells and cross cell substrates. This amoeboid-like movement uses a parasite adhesin from the thrombospondin-related anonymous protein (TRAP) family and a set of proteins linking the extracellular adhesin, via an actin-myosin motor, to the inner membrane complex. The Plasmodium blood stage merozoite, however, does not exhibit gliding motility. Here we show that homologues of the key proteins that make up the motor complex, including the recently identified glideosome-associated proteins 45 and 50 (GAP40 and GAP50), are present in P. falciparum merozoites and appear to function in erythrocyte invasion. Furthermore, we identify a merozoite TRAP homologue, termed MTRAP, a micronemal protein that shares key features with TRAP, including a thrombospondin repeat domain, a putative rhomboid-protease cleavage site, and a cytoplasmic tail that, in vitro, binds the actin-binding protein aldolase. Analysis of other parasite genomes shows that the components of this motor complex are conserved across diverse Apicomplexan genera. Conservation of the motor complex suggests that a common molecular mechanism underlies all Apicomplexan motility, which, given its unique properties, highlights a number of novel targets for drug intervention to treat major diseases of humans and livestock.

Received for publication, September 7, 2005 , and in revised form, November 28, 2005.

^* This work was supported in part by the National Health and Medical Research Council (NHMRC) and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ Supported by a Peter Doherty Fellowship from the NHMRC.

² These authors contributed equally to this work.

³ Supported by the Fonds de la Recherche en Santé du Québec.

⁴ A Howard Hughes International Fellow. To whom correspondence should be addressed: The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. Tel.: 61393452555; Fax: 61393470852; E-mail: cowman{at}wehi.edu.au.

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