Evolutionary adaptations of doublet microtubules in trypanosomatid parasites

The movement and pathogenicity of trypanosomatid species, the causative agents of trypanosomiasis and leishmaniasis, are dependent on a flagellum that contains an axoneme of dynein-bound doublet microtubules (DMTs). In this work, we present cryo–electron microscopy structures of DMTs from two trypanosomatid species, Leishmania tarentolae and Crithidia fasciculata, at resolutions up to 2.7 angstrom. The structures revealed 27 trypanosomatid-specific microtubule inner proteins, a specialized dynein-docking complex, and the presence of paralogous proteins that enable higher-order periodicities or proximal-distal patterning. Leveraging the genetic tractability of trypanosomatid species, we quantified the location and contribution of each structure-identified protein to swimming behavior. Our study shows that proper B-tubule closure is critical for flagellar motility, exemplifying how integrating structural identification with systematic gene deletion can dissect individual protein contributions to flagellar motility. Trypanosomatids are parasites transmitted by insects that cause lethal and debilitating diseases in humans and other vertebrates. These parasites depend on a tail-like oscillating appendage called a flagellum to travel within their insect carriers or vertebrate hosts. The movement of the flagellum is generated by an enormous internal protein-based machine called the axoneme. Xia et al. used high-resolution cryo–electron microscopy to reveal the intricate structure and connections of the flagellum components of Trypanosoma brucei. They identified components specific to the parasite and uncovered how molecular motors drive the movement. Doran et al. defined individual components of the axoneme and identified a cluster of proteins that are essential for the parasite’s ability to swim properly. Together, these studies shed light on flagellum biology, evolution, and function; enhance our understanding of parasite biology; and highlight potential drug targets to prevent parasite spread and infection. —Stella M. Hurtley