Structures of Native Doublet Microtubules from Trichomonas vaginalis Reveal Parasite-Specific Proteins as Potential Drug Targets

Alexander Stevens; Saarang Kashyap; Ethan H Crofut; Shuqi E Wang; Katherine A Muratore; Patricia J Johnson; Z Hong Zhou

doi:10.21203/rs.3.rs-4632384/v1

Structures of Native Doublet Microtubules from Trichomonas vaginalis Reveal Parasite-Specific Proteins as Potential Drug Targets

Res Sq [Preprint]. 2024 Sep 2:rs.3.rs-4632384. doi: 10.21203/rs.3.rs-4632384/v1.

Authors

Alexander Stevens^{1

2

3}, Saarang Kashyap^{1

2}, Ethan H Crofut^{1

2}, Shuqi E Wang¹, Katherine A Muratore¹, Patricia J Johnson¹, Z Hong Zhou^{1

2

3}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Abstract

Doublet microtubules (DMTs) are flagellar components required for the protist Trichomonas vaginalis (Tv) to swim through the human genitourinary tract to cause trichomoniasis, the most common non-viral sexually transmitted disease. Lack of DMT structures has prevented structure-guided drug design to manage Tv infection. Here, we determined the cryo-EM structure of native Tv-DMTs, identifying 29 unique proteins, including 18 microtubule inner proteins and 9 microtubule outer proteins. While the A-tubule is simplistic compared to DMTs of other organisms, the B-tubule features specialized, parasite-specific proteins, such as TvFAP40 and TvFAP35 that form filaments near the inner and outer junctions, respectively, to stabilize DMTs and enable Tv locomotion. Notably, a small molecule, assigned as IP6, is coordinated within a pocket of TvFAP40 and has characteristics of a drug molecule. This first atomic model of the Tv-DMT highlights the diversity of eukaryotic motility machinery and provides a structural framework to inform rational design of therapeutics.

Keywords: Trichomonas vaginalis; antiparasitic; cryo-EM; doublet microtubule; trichomoniasis.

Publication types

Preprint

Abstract

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