A DOC2 Protein Identified by Mutational Profiling Is Essential for Apicomplexan Parasite Exocytosis

• Published in: Science (American Association for the Advancement of Science) 2012-01, Vol.335 (6065), p.218-221
• Main Authors: Farrell, Andrew, Thirugnanam, Sivasakthivel, Lorestani, Alexander, Dvorin, Jeffrey D., Eidell, Keith P., Ferguson, David J.P., Anderson-White, Brooke R., Duraisingh, Manoj T., Marth, Gabor T., Gubbels, Marc-Jan
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Biological and medical sciences; Calcium - metabolism; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell adhesion & migration; Cell Line; Cell physiology; Cellular biology; Exocytosis; Fundamental and applied biological sciences. Psychology; Genes, Protozoan; Genetic Complementation Test; Genome, Protozoan; Genotype & phenotype; Humans; Malaria; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Movement; Mutagenesis; Organelles; Organelles - metabolism; Parasite hosts; Parasites; Phenotypes; Plasmodium falciparum; Plasmodium falciparum - genetics; Plasmodium falciparum - growth & development; Plasmodium falciparum - physiology; Point Mutation; Protein Structure, Tertiary; Proteins; Protozoan Proteins - chemistry; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Recombinant Fusion Proteins - metabolism; Schizonts; Secretion; Secretion. Exocytosis; Sequencing; Toxoplasma - genetics; Toxoplasma - growth & development; Toxoplasma - physiology; Toxoplasma - ultrastructure; Toxoplasma gondii
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1210829

Exocytosis is essential to the lytic cycle of apicomplexan parasites and required for the pathogenesis of toxoplasmosis and malaria. DOC2 proteins recruit the membrane fusion machinery required for exocytosis in a Ca²⁺-dependent fashion. Here, the phenotype of a Toxoplasma gondii conditional mutant impaired in host cell invasion and egress was pinpointed to a defect in secretion of the micronemes, an apicomplexan-specific organelle that contains adhesion proteins. Whole-genome sequencing identified the etiological point mutation in TgDOC2.1. A conditional allele of the orthologous gene engineered into Plasmodium falciparum was also defective in microneme secretion. However, the major effect was on invasion, suggesting that microneme secretion is dispensable for Plasmodium egress.