Characterizing the unique myosin motors driving motility and active host cell invasion by apicomplexan parasites

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dc.contributor.authorPowell, Cameron
dc.contributor.supervisorBoulanger, Martin. J.
dc.date.accessioned2020-05-04T22:20:59Z
dc.date.available2020-05-04T22:20:59Z
dc.date.copyright2020en_US
dc.date.issued2020-05-04
dc.degree.departmentDepartment of Biochemistry and Microbiologyen_US
dc.degree.levelDoctor of Philosophy Ph.D.en_US
dc.description.abstractPhylum Apicomplexa comprises several thousand parasitic protozoans that cause significant disease in humans and animals worldwide. Of particular relevance to human health are Plasmodium spp., the causative agents of malaria; and Toxoplasma gondii, which infects approximately 30% of all humans on earth, and causes serious disease in immunocompromised individuals and neonatally infected fetuses. Central to the pathogenesis of apicomplexans is a unique form of substrate-dependent locomotion termed “gliding motility”, which is essential for traversing the environment and actively invading host cells. Driving motility is the class-XIV unconventional myosin motor (MyoA), which is notably divergent from canonical myosins in that it lacks a “tail” and conventional sequence motifs in both the neck and motor regions. Thus, the mechanisms that enable MyoA to function with a step size and velocity similar to canonical human myosins are not well understood. Over the past 2 decades, the apicomplexan research community has identified many of the components involved in gliding motility, resulting in a functional model of MyoA and accessory proteins forming the “glideosome” macromolecular complex. However, there was still relatively little known about the unique physical processes that drive force production and transduction in the apicomplexan motor complex. Thus, I set out to use structural and biophysical methods to interrogate this divergent molecular motor, and provide the first high-resolution model of apicomplexan motility. Towards this goal, I first used structural and biophysical methods to establish the most complete model to date of class-XIV motor complex assembly, answering key questions about the interface between MyoA and its accessory proteins. To understand the unique molecular basis of force production in apicomplexan motors, I then solved the first ever crystal structure of a class-XIV myosin, MyoA from T. gondii. Supplementing this structure with further biophysical data, I was able to determine the functional consequences of class-defining sequence polymorphisms, and elucidate the basis of phosphorylation-dependent motor regulation. The systematic dissection of apicomplexan motor complexes described herein provides crucial insight into a fundamental biological process, and may help overcome existing barriers for targeted therapeutic development.en_US
dc.description.scholarlevelGraduateen_US
dc.identifier.bibliographicCitationPowell CJ, et al. (2018) Structural and mechanistic insights into the function of the unconventional class XIV myosin MyoA from Toxoplasma gondii. Proc Natl Acad Sci U S A 115(45):E10548-E10555en_US
dc.identifier.bibliographicCitationPowell CJ, et al. (2017) Dissecting the molecular assembly of the Toxoplasma gondii MyoA motility complex. J Biol Chem 292(47):19469–19477en_US
dc.identifier.urihttp://hdl.handle.net/1828/11716
dc.languageEnglisheng
dc.language.isoenen_US
dc.rightsAvailable to the World Wide Weben_US
dc.subjectToxoplasma gondiien_US
dc.subjectMalariaen_US
dc.subjectPlasmodiumen_US
dc.subjectMyosinen_US
dc.subjectMotilityen_US
dc.subjectApicomplexaen_US
dc.subjectX-ray crystallographyen_US
dc.subjectHDX-MSen_US
dc.subjectITCen_US
dc.subjectStructural biologyen_US
dc.subjectProteinen_US
dc.titleCharacterizing the unique myosin motors driving motility and active host cell invasion by apicomplexan parasitesen_US
dc.typeThesisen_US

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