A conserved molecular motor drives cell invasion and gliding motility across malaria life cycle stages and other apicomplexan parasites.
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.
Baum
Jake
J
Division of Infection and Immunity, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Richard
Dave
D
Healer
Julie
J
Rug
Melanie
M
Krnajski
Zita
Z
Gilberger
Tim-Wolf
TW
Green
Judith L
JL
Holder
Anthony A
AA
Cowman
Alan F
AF
D000199:Actins / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism; D001665:Binding Sites; D003593:Cytoplasm / Q000378:metabolism; D030562:Databases, Protein; D004591:Electrophoresis, Polyacrylamide Gel; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry; D005822:Genetic Vectors; D016678:Genome; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008288:Malaria / Q000469:parasitology*; D008565:Membrane Proteins / Q000502:physiology; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D020409:Molecular Motor Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D009068:Movement; D005810:Multigene Family; D010961:Plasmodium / Q000472:pathogenicity*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000502:physiology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D034101:Sporozoites / Q000378:metabolism*; D019699:Thrombospondins / Q000737:chemistry; D013997:Time Factors; D014122:Toxoplasma / Q000472:pathogenicity*; D014162:Transfection
D000199:Actins; D000953:Antigens, Protozoan; D008565:Membrane Proteins; D020409:Molecular Motor Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D019699:Thrombospondins; C509918:glideosome-associated protein 45, Plasmodium falciparum; C509919:glideosome-associated protein 50, Plasmodium falciparum; C069428:thrombospondin-related adhesive protein, protozoan; D049452:Green Fluorescent Proteins; D005634:Fructose-Bisphosphate Aldolase