title: Malaria parasite CelTOS targets the inner leaflet of cell membranes for pore-dependent disruption.
abstract: Apicomplexan parasites contain a conserved protein CelTOS that, in malaria parasites, is essential for traversal of cells within the mammalian host and arthropod vector. However, the molecular role of CelTOS is unknown because it lacks sequence similarity to proteins of known function. Here, we determined the crystal structure of CelTOS and discovered CelTOS resembles proteins that bind to and disrupt membranes. In contrast to known membrane disruptors, CelTOS has a distinct architecture, specifically binds phosphatidic acid commonly present within the inner leaflet of plasma membranes, and potently disrupts liposomes composed of phosphatidic acid by forming pores. Microinjection of CelTOS into cells resulted in observable membrane damage. Therefore, CelTOS is unique as it achieves nearly universal inner leaflet cellular activity to enable the exit of parasites from cells during traversal. By providing novel molecular insight into cell traversal by apicomplexan parasites, our work facilitates the design of therapeutics against global pathogens.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Jimah
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States.
authors.forename: Nichole D
authors.initials: ND
authors.lastname: Salinas
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, United States.|Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Sala-Rabanal
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States.
authors.forename: Nathaniel G
authors.initials: NG
authors.lastname: Jones
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States.
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, United States.|Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, United States.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, United States.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Schlesinger
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States.|Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, United States.
authors.forename: Niraj H
authors.identifier: 0000-0002-2689-1337
authors.initials: NH
authors.lastname: Tolia
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010966:Plasmodium vivax / Q000472:pathogenicity*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism*; D037521:Virulence Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C000624324:CelTOS protein, Plasmodium vivax; D015800:Protozoan Proteins; D037521:Virulence Factors
keywords: E. coli; apicomplexan; biophysics; infectious disease; malaria; membrane; microbiology; pore; structural biology; vaccine; vivax; xenopus