Implications of conformational flexibility, lipid binding, and regulatory domains in cell-traversal protein CelTOS for apicomplexan migration.

TitleImplications of conformational flexibility, lipid binding, and regulatory domains in cell-traversal protein CelTOS for apicomplexan migration.
Publication TypeJournal Article
Year of Publication2022
AuthorsKumar, H, Jimah, JR, Misal, SA, Salinas, ND, Fried, M, Schlesinger, PH, Tolia, NH
JournalJ Biol Chem
Volume298
Issue9
Pagination102241
Date Published2022 Sep
ISSN1083-351X
KeywordsAmino Acids, Animals, Disulfides, Humans, Lipids, Malaria, Malaria Vaccines, Protozoan Proteins, Sporozoites
Abstract

<p>Malaria and other apicomplexan-caused diseases affect millions of humans, agricultural animals, and pets. Cell traversal is a common feature used by multiple apicomplexan parasites to migrate through host cells and can be exploited to develop therapeutics against these deadly parasites. Here, we provide insights into the mechanism of the Cell-traversal protein for ookinetes and sporozoites (CelTOS), a conserved cell-traversal protein in apicomplexan parasites and malaria vaccine candidate. CelTOS has previously been shown to form pores in cell membranes to enable traversal of parasites through cells. We establish roles for the distinct protein regions of Plasmodium vivax CelTOS and examine the mechanism of pore formation. We further demonstrate that CelTOS dimer dissociation is required for pore formation, as disulfide bridging between monomers inhibits pore formation, and this inhibition is rescued by disulfide-bridge reduction. We also show that a helix-destabilizing amino acid, Pro127, allows CelTOS to undergo significant conformational changes to assemble into pores. The flexible C terminus of CelTOS is a negative regulator that limits pore formation. Finally, we highlight that lipid binding is a prerequisite for pore assembly as mutation of a phospholipids-binding site in CelTOS resulted in loss of lipid binding and abrogated pore formation. These findings identify critical regions in CelTOS and will aid in understanding the egress mechanism of malaria and other apicomplexan parasites as well as have implications for studying the function of other essential pore-forming proteins.</p>

DOI10.1016/j.jbc.2022.102241
Alternate JournalJ Biol Chem
PubMed ID35809642
PubMed Central IDPMC9400078
Grant ListR01 AI137162 / AI / NIAID NIH HHS / United States