Actin depolymerizing factor controls actin turnover and gliding motility in<i>Toxoplasma gondii</i>

Mehta, Simren; Sibley, L. David

doi:10.1091/mbc.e10-12-0939

Cited by 57 publications

(93 citation statements)

References 38 publications

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“…Although ADF2 is thought to function in sexual stages of parasite development (10,22), studies in the mouse malaria parasite Plasmodium berghei and malaria-related parasite Toxoplasma gondii have established that ADF1 (and its ortholog TgADF) is essential for parasite viability (10) and actin filament turnover (23). Biochemical studies of recombinant ADF1 from the most virulent human parasite, P. falciparum, have suggested several unique properties.…”

mentioning

confidence: 99%

Minimal requirements for actin filament disassembly revealed by structural analysis of malaria parasite actin-depolymerizing factor 1

Wong

Skau

Marapana

et al. 2011

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

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Malaria parasite cell motility is a process that is dependent on the dynamic turnover of parasite-derived actin filaments. Despite its central role, actin's polymerization state is controlled by a set of identifiable regulators that is markedly reduced compared with those of other eukaryotic cells. In Plasmodium falciparum, the most virulent species that affects humans, this minimal repertoire includes two members of the actin-depolymerizing factor/cofilin (AC) family of proteins, P. falciparum actin-depolymerizing factor 1 (PfADF1) and P. falciparum actin-depolymerizing factor 2. This essential class of actin regulator is involved in the control of filament dynamics at multiple levels, from monomer binding through to filament depolymerization and severing. Previous biochemical analyses have suggested that PfADF1 sequesters monomeric actin but, unlike most eukaryotic counterparts, has limited potential to bind or depolymerize filaments. The molecular basis for these unusual properties and implications for parasite cell motility have not been established. Here we present the crystal structure of an apicomplexan AC protein, PfADF1. We show that PfADF1 lacks critical residues previously implicated as essential for AC-mediated actin filament binding and disassembly, having a substantially reduced filament-binding loop and C-terminal α4 helix. Despite this divergence in structure, we demonstrate that PfADF1 is capable of efficient actin filament severing. Furthermore, this severing occurs despite PfADF1's low binding affinity for filaments. Comparative structural analysis along with biochemical and microscopy evidence establishes that severing is reliant on the availability of an exposed basic residue in the filament-binding loop, a conserved minimal requirement that defines AC-mediated filament disassembly across eukaryotic cells.crystallography | circular dichroism spectroscopy | total internal reflection fluorescence microscopy | gliding motility | tight junction T he eukaryotic parasites from the genus Plasmodium that cause malaria disease require rapid cell movement to complete development, a process dependent on a parasite-derived actomyosin motor (1, 2). Short, dynamic actin filaments engage with an internal single-headed myosin, generating force that propels parasites along substrates or into host cells (reviewed in ref.3). Drugs that stall actin filament growth or stabilize them from depolymerization prevent parasite motility when used at high concentrations, demonstrating the importance of dynamic actin (4-8). Despite this central role, however, actin filament turnover across all Apicomplexa, the phylum to which malaria parasites belong, is controlled by only a minimal set of identifiable regulators (3, 9). In Plasmodium falciparum, the most virulent species causing malaria disease, this minimal set includes two members of the actin-depolymerization factor/cofilin (AC) family of proteins, actin-depolymerization factor 1 (ADF1) and actindepolymerization factor 2 (ADF2) (10).AC proteins function as key regula...

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confidence: 99%

Minimal requirements for actin filament disassembly revealed by structural analysis of malaria parasite actin-depolymerizing factor 1

Wong

Skau

Marapana

et al. 2011

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

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“…Plusieurs protéines liant l'actine et conservées à travers le phylum ont d'ailleurs récemment été décrites, et leur rôle s'est révélé critique pour la motilité et l'invasion du toxoplasme. Les formines TgFRM1 (Toxoplasma formin 1) et TgFRM2 sont impliquées dans la polymérisation des filaments d'actine [16,17], alors que la cofiline TgADF (Toxoplasma acting depolymerizing factor) joue un rôle dans leur dépolymérisation [18,19] et que la profiline TgPRF (Toxoplasma profilin) séquestre les monomères [17,20] (Figure 2B). Normalement, formine et profiline fonctionnent de façon coopérative afin de stimuler la formation du filament d'actine de part et d'autre du domaine FH2 (formin homology 2 domain) de la formine ( Figure 2B).…”

Section: Ancrage Et Production Du Mouvementunclassified

“…Récemment, des filaments d'actine ont pu être visualisés par immunofluorescence chez le toxoplasme suite à la délétion conditionnelle du facteur de dépolymérisation des filaments d'actine ADF. Comme attendu, ces parasites se sont révélés incapables d'envahir de façon efficace des cellules hôtes et d'en sortir [19]. du mouvement à une vitesse d'environ 5 μm/s, ce qui est compatible avec la vitesse de déplacement des tachyzoïtes [30].…”

Section: Ancrage Et Production Du Mouvementunclassified

Un complexe moléculaire unique à l’origine de la motilité et de l’invasion des Apicomplexes

Frénal

Soldati‐Favre

2013

Med Sci (Paris)

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“…In those same assays, the biochemical properties of TgPRF indicate that the protein sequestrates actin monomers and does not contribute to polymerization (Skillman et al, 2012). TgADF is another highly potent factor that leads to actin depolymerization, and deletion of the gene results in the accumulation of actin filaments in T. gondii (Mehta and Sibley, 2011). This abnormal actin polymerization causes severe defects in egress, gliding, and host cell invasion.…”

Section: Actin Dynamicsmentioning

confidence: 99%

“…Gliding motility, more directly myosin ATPase activity, and actin polymerization need to be tightly regulated in a timely and spatial fashion. Several key regulators of actin dynamics including profilin (PRF), formins (FRMs), and actin depolymerization factor (ADF) were found to govern parasite motility (Baum et al, 2008;Daher et al, 2010;Mehta and Sibley, 2011;Plattner et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Does protein phosphorylation govern host cell entry and egress by the Apicomplexa?

Jacot

Soldati‐Favre

2012

International Journal of Medical Microbiology

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a b s t r a c tMembers of the phylum Apicomplexa are responsible for a wide range of diseases in humans and animals. The absence of an effective vaccine or safe curing drugs and the continuous emergence of resistant parasites to available treatments impose a high demand on the identification of novel targets for intervention against the apicomplexans. Protein kinases are considered attractive potential therapeutic targets not only against cancers but also to combat infectious diseases. The scope and aim of this review is to report on the recent progress in dissecting the impact of protein phosphorylation in regulating motility and invasion.

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Actin depolymerizing factor controls actin turnover and gliding motility inToxoplasma gondii

Cited by 57 publications

References 38 publications

Minimal requirements for actin filament disassembly revealed by structural analysis of malaria parasite actin-depolymerizing factor 1

Minimal requirements for actin filament disassembly revealed by structural analysis of malaria parasite actin-depolymerizing factor 1

Un complexe moléculaire unique à l’origine de la motilité et de l’invasion des Apicomplexes

Does protein phosphorylation govern host cell entry and egress by the Apicomplexa?

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