Functions of myosin motors tailored for parasitism

Mueller, Christina; Graindorge, Arnault; Soldati‐Favre, Dominique

doi:10.1016/j.mib.2017.11.003

Cited by 14 publications

(22 citation statements)

References 72 publications

(61 reference statements)

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“…2, (33)). Additionally, class XIV myosins have an N-terminal SH3 domain, the role of which is unclear but could be related to the regulation of myosin function during different stages of the parasite life cycle (34). Our actomyosin rigor structure shows that neither the SH3 domain nor the N-terminal helix is in direct contact with the actin filament (Fig.…”

Section: High-resolution Structures Of Malaria Parasite Actomyosin Anmentioning

confidence: 91%

High-resolution structures of malaria parasite actomyosin and actin filaments

Vahokoski

Calder

Lopez

et al. 2020

Preprint

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AbstractMalaria is responsible for half a million deaths annually and poses a huge economic burden on the developing world. The mosquito-borne parasites (Plasmodium spp.) that cause the disease depend upon an unconventional actomyosin motor for both gliding motility and host cell invasion. The motor system, often referred to as the glideosome complex, remains to be understood in molecular terms and is an attractive target for new drugs that might block the infection pathway. Here, we present the first high-resolution structure of the actomyosin motor complex from Plasmodium falciparum. Our structure includes the malaria parasite actin filament (PfAct1) complexed with the myosin motor (PfMyoA) and its two associated light-chains. The high-resolution core structure reveals the PfAct1:PfMyoA interface in atomic detail, while at lower-resolution, we visualize the PfMyoA light-chain binding region, including the essential light chain (PfELC) and the myosin tail interacting protein (PfMTIP). Finally, we report a bare PfAct1 filament structure at an improved resolution, which gives new information about the nucleotide-binding site, including the orientation of the ATP/ADP sensor, Ser15, and the presence of a channel, which we propose as a possible phosphate exit path after ATP hydrolysis.Significance statementWe present the first structure of the malaria parasite motor complex; actin 1 (PfAct1) and myosin A (PfMyoA) with its two light chains. We also report a high-resolution structure of filamentous PfAct1 that reveals new atomic details of the ATPase site, including a channel, which may provide an exit route for phosphate and explain why phosphate release is faster in PfAct1 compared to canonical actins. PfAct1 goes through no conformational changes upon PfMyoA binding. Our PfMyoA structure also superimposes with a recent crystal structure of PfMyoA alone, though there are small but important conformational changes at the interface. Our structures serve as an excellent starting point for drug design against malaria, which is one of the most devastating infectious diseases.

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Section: High-resolution Structures Of Malaria Parasite Actomyosin Anmentioning

confidence: 91%

High-resolution structures of malaria parasite actomyosin and actin filaments

Vahokoski

Calder

Lopez

et al. 2020

Preprint

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“…T. gondii has the largest repertoire of myosins among Apicomplexa, with 11 unique isoforms that are implicated in numerous essential processes including cell division, organellar inheritance, motility, and host cell invasion (4,5). The major myosin driving parasite motility and host cell invasion, MyoA, belongs to class XIV of the myosin superfamily, which exists only in apicomplexans and select ciliates (4,5).…”

mentioning

confidence: 99%

“…gondii has the largest repertoire of myosins among Apicomplexa, with 11 unique isoforms that are implicated in numerous essential processes including cell division, organellar inheritance, motility, and host cell invasion (4,5). The major myosin driving parasite motility and host cell invasion, MyoA, belongs to class XIV of the myosin superfamily, which exists only in apicomplexans and select ciliates (4,5). Of the class XIV isoforms, MyoA is the most well conserved across the phylum, likely because of its central role in motility and invasion (6); depletion of MyoA in T. gondii severely impairs both of these processes (7)(8)(9)(10).…”

mentioning

confidence: 99%

Structural and mechanistic insights into the function of the unconventional class XIV myosin MyoA from Toxoplasma gondii

Powell

Ramaswamy

Kelsen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Parasites of the phylum Apicomplexa are responsible for significant morbidity and mortality on a global scale. Central to the virulence of these pathogens are the phylum-specific, unconventional class XIV myosins that power the essential processes of parasite motility and host cell invasion. Notably, class XIV myosins differ from human myosins in key functional regions, yet they are capable of fast movement along actin filaments with kinetics rivaling previously studied myosins. Toward establishing a detailed molecular mechanism of class XIV motility, we determined the 2.6-Å resolution crystal structure of the Toxoplasma gondii MyoA (TgMyoA) motor domain. Structural analysis reveals intriguing strategies for force transduction and chemomechanical coupling that rely on a divergent SH1/SH2 region, the class-defining "HYAG"-site polymorphism, and the actin-binding surface. In vitro motility assays and hydrogen-deuterium exchange coupled with MS further reveal the mechanistic underpinnings of phosphorylation-dependent modulation of TgMyoA motility whereby localized regions of increased stability and order correlate with enhanced motility. Analysis of solvent-accessible pockets reveals striking differences between apicomplexan class XIV and human myosins. Extending these analyses to high-confidence homology models of Plasmodium and Cryptosporidium MyoA motor domains supports the intriguing potential of designing class-specific, yet broadly active, apicomplexan myosin inhibitors. The successful expression of the functional TgMyoA complex combined with our crystal structure of the motor domain provides a strong foundation in support of detailed structure-function studies and enables the development of small-molecule inhibitors targeting these devastating global pathogens. myosin | Apicomplexa | Toxoplasma gondii | motility | X-ray crystallography

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“…This movement, governed by an acto‐myosin motor, involves dozens of proteins that appear (so far) well conserved between apicomplexan species (Boucher and Bosch, 2015; Frenal et al., 2017; Mueller et al., 2017). Whether the gliding components are conserved also in gregarines that move by gliding (i.e., most eugregarines) remains to be established.…”

Section: Why Should We Study Gregarines?mentioning

confidence: 99%

Why the –omic future of Apicomplexa should include gregarines

Boisard

Florent

2020

Biology of the Cell

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Gregarines, a polyphyletic group of apicomplexan parasites infecting mostly non‐vertebrates hosts, remains poorly known at taxonomic, phylogenetic and genomic levels. However, it represents an essential group for understanding evolutionary history and adaptive capacities of apicomplexan parasites to the remarkable diversity of their hosts. Because they have a mostly extracellular lifestyle, gregarines have developed other cellular developmental forms and host–parasite interactions, compared with their much better studied apicomplexan cousins, intracellular parasites of vertebrates (Hemosporidia, Coccidia, Cryptosporidia). This review highlights the promises offered by the molecular exploration of gregarines, that have been until now left on the side of the road of the comparative –omic exploration of apicomplexan parasites. Elucidating molecular bases for both their ultrastructural, functional and behavioural similarities and differences, compared with those of the typical apicomplexan models, is expected to provide entirely novel clues on the adaptive capacities developed by Apicomplexa over evolution. A challenge remains to identify which gregarines should be explored in priority, as recent metadata from open and host‐associated environments have confirmed how underestimated is our current view on true gregarine biodiversity. It is now time to turn to gregarines to widen the currently highly skewed view we have of adaptive mechanisms developed by Apicomplexa.

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Functions of myosin motors tailored for parasitism

Cited by 14 publications

References 72 publications

High-resolution structures of malaria parasite actomyosin and actin filaments

High-resolution structures of malaria parasite actomyosin and actin filaments

Structural and mechanistic insights into the function of the unconventional class XIV myosin MyoA from Toxoplasma gondii

Why the –omic future of Apicomplexa should include gregarines

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