Calcium-dependent phosphorylation alters class XIVa myosin function in the protozoan parasite<i>Toxoplasma gondii</i>

Tang, Qian; Andenmatten, Nicole; Triana, Miryam Andrea Hortua; Deng, Bin; Meissner, Markus; Moreno, Silvia N.J.; Ballif, Bryan A.; Ward, Gary E.

doi:10.1091/mbc.e13-11-0648

Cited by 41 publications

(54 citation statements)

References 75 publications

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“…By contrast, the calcium-dependent phosphorylation of TgMYOA affects its motor function 65,66 . In addition, acylation has a crucial role in the positioning of the glideosome within the pellicle.…”

Section: Conoidmentioning

confidence: 97%

Gliding motility powers invasion and egress in Apicomplexa

et al. 2017

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| Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa -a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) -have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells. NATURE REVIEWS | MICROBIOLOGYADVANCE ONLINE PUBLICATION | 1 REVIEWS © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . ToxoplasmosisA food-borne infection caused by the parasite Toxoplasma gondii. The infection is usually mild or even asymptomatic, but can have serious consequences in patients who are immunocompromised and for the fetus in the case of primary infection during pregnancy. SporozoitesThe infectious and motile stage produced in oocysts and transmitted by the definitive host. TachyzoitesThe motile and fast-replicative stage of Toxoplasma gondii that is able to invade any nucleated cell in the host. MerozoitesThe stage of Plasmodium spp. that infects erythrocytes, in which it initiates a new asexual life cycle. Actomyosin systemA complex that comprises actin filaments, myosin and associated proteins, and that is involved in movement. GlideosomeA molecular complex that powers gliding motility in apicomplexan parasites.motility, invasion and egress. In this Review, we focus primarily on the T. gondii tachyzoite, for which functional studies were first carried out, and we compare and contrast this with the motile stages of malaria parasites -the sporozoite, merozoite and ookinete.Emergence of the capping model The motility of Apicomplexa (historically named Sporozoa) has caught the attention of scientists for more than a century 8 and was named gliding motility early on, on the basis of microscopic observations Nature Reviews | Microbiology www.nature.com/nrmicro © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . of live specimens (FIG. 2; Supplementary information S1-S5 (movies)). This mode of motility differs substantially to amoeboid motion involving pseudopods, and from the ciliary and flagellar motion used by most unicellular organisms. The main hypothesis to explain gliding motility in the early days was slime secretion, as seen in slugs; ...

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Section: Conoidmentioning

confidence: 97%

Gliding motility powers invasion and egress in Apicomplexa

et al. 2017

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“…A similar study looked phosphorylation sites on the major motor protein driving gliding motility, TgMyoA. By complementing a conditional knock-down of TgMyoA, the authors could demonstrate that the motor is subtly regulated by calcium-dependent phosphorylation [107]. Crucially, the defects in ionophore-induced egress displayed by non-phosphorylatable alleles could be rescued by expression of a MyoA bearing phospho-mimetic mutations [107].…”

Section: Ca2+ Signaling and Its Biological Downstream Effects In Amentioning

confidence: 99%

“…By complementing a conditional knock-down of TgMyoA, the authors could demonstrate that the motor is subtly regulated by calcium-dependent phosphorylation [107]. Crucially, the defects in ionophore-induced egress displayed by non-phosphorylatable alleles could be rescued by expression of a MyoA bearing phospho-mimetic mutations [107]. It is conceivable that the important phenotypes that have been attributed to CDPKs are the consequence of many subtle regulatory functions.…”

Section: Ca2+ Signaling and Its Biological Downstream Effects In Amentioning

confidence: 99%

The calcium signaling toolkit of the Apicomplexan parasites Toxoplasma gondii and Plasmodium spp

2015

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Apicomplexan parasites have complex life cycles, frequently split between different hosts and reliant on rapid responses as the parasites react to changing environmental conditions. Calcium ion (Ca2+) signaling is consequently essential for the cellular and developmental changes that support apicomplexan parasitism. Apicomplexan genomes reveal a rich repertoire of genes involved in calcium signaling, although many of the genes responsible for observed physiological changes remain unknown. There is evidence, for example, for the presence of a nifedipine-sensitive calcium entry mechanism in Toxoplasma, but the molecular components involved in Ca2+ entry in both Toxoplasma and Plasmodium, have not been identified. The major calcium stores are the endoplasmic reticulum (ER), the acidocalcisomes, and the plant-like vacuole in Toxoplasma, or the food vacuole in Plasmodium spp. Pharmacological evidence suggests that Ca2+ release from intracellular stores may be mediated by inositol 1,4,5-trisphosphate (IP3) or cyclic ADP ribose (cADPR) although there is no molecular evidence for the presence of receptors for these second messengers in the parasites. Several Ca2+-ATPases are present in apicomplexans and a putative mitochondrial Ca2+/H+ exchanger has been identified. Apicomplexan genomes contain numerous genes encoding Ca2+-binding proteins, with the notable expansion of calcium-dependent protein kinases (CDPKs), whose study has revealed novel roles in gliding motility, microneme secretion, host cell invasion and egress, and parasite differentiation. Microneme secretion has also been shown to depend on the C2 domain containing protein DOC2 in both Plasmodium spp. and Toxoplasma, providing further evidence for the complex transduction of Ca2+ signals in these organisms. The characterization of these pathways could lead to the discovery of novel drug targets and to a better understanding of the role of Ca2+ in these parasites.

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“…Multiple phosphorylation sites have been identified for TgMyoA and the calcium-dependent protein kinase 3 (TgCDPK3) was shown to be responsible for TgMyoA phosphorylation, thereby facilitating parasite motility and host cell egress [42]. The small molecule enhancer compound 130038 was found to cause a calcium-dependent increase in TgMyoA phosphorylation, and upon mutation of the major TgMyoA phospho-sites calcium-induced host cell egress was delayed [43]. Moreover the small-molecule inhibitors tachypleginA and its analogues were shown to directly and covalently bind C58 of TgMLC1, thereby inhibiting motility and invasion [44].…”

Section: Glideosome-associated Myosins Of Apicomplexamentioning

confidence: 99%