Plasmodium Sporozoite Motility Is Modulated by the Turnover of Discrete Adhesion Sites

Münter, Sylvia; Sabass, Benedikt; Selhuber‐Unkel, Christine; Kudryashev, Mikhail; Hegge, Stephan; Engel, Ulrike; Spatz, Joachim P.; Matuschewski, Kai; Schwarz, Ulrich S.; Frischknecht, Friedrich

doi:10.1016/j.chom.2009.11.007

Cited by 166 publications

(300 citation statements)

References 43 publications

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“…The remaining C-terminal segment between the TRAP TSR domain and membrane-spanning domain consists predominantly of proline and polar residues, is likely to be natively unstructured, and to project the ligand-binding domains in TRAP above the protective sheath formed by the CS protein. TRAP has been shown to mediate gliding motility through a "stick-and-slip" process in which different regions of the sporozoite surface alternate between being attached and detached from the substrate (20). Our findings that TRAP exists in both closed and open conformations and that the open, putative high-affinity conformation is linked to TRAP ectodomain extension provides a mechanism for cytoskeletal regulation of stick-and-slip motility.…”

Section: Resultsmentioning

confidence: 67%

Shape change in the receptor for gliding motility in Plasmodium sporozoites

Song

Koksal

et al. 2012

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

142

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Sporozoite gliding motility and invasion of mosquito and vertebrate host cells in malaria is mediated by thrombospondin repeat anonymous protein (TRAP). Tandem von Willebrand factor A (VWA) and thrombospondin type I repeat (TSR) domains in TRAP connect through proline-rich stalk, transmembrane, and cytoplasmic domains to the parasite actin-dependent motility apparatus. We crystallized fragments containing the VWA and TSR domains from Plasmodium vivax and Plasmodium falciparum in different crystal lattices. TRAP VWA domains adopt closed and open conformations, and bind a Mg 2+ ion at a metal ion-dependent adhesion site implicated in ligand binding. Metal ion coordination in the open state is identical to that seen in the open high-affinity state of integrin I domains. The closed VWA conformation associates with a disordered TSR domain. In contrast, the open VWA conformation crystallizes with an extensible β ribbon and ordered TSR domain. The extensible β ribbon is composed of disulfide-bonded segments N-and C-terminal to the VWA domain that are largely drawn out of the closed VWA domain in a 15 Å movement to the open conformation. The extensible β ribbon and TSR domain overlap at a conserved interface. The VWA, extensible β ribbon, and TSR domains adopt a highly elongated overall orientation that would be stabilized by tensile force exerted across a ligand-receptor complex by the actin motility apparatus of the sporozoite. Our results provide insights into regulation of "stick-and-slip" parasite motility and for development of sporozoite subunit vaccines. M osquitoes transmit malaria to humans via sporozoites. Sporozoites are important targets of pre-erythrocytic malaria vaccines. However, we know little about the structure and arrangement of the two most important vaccine targets on sporozoite surfaces, the circumsporozoite (CS) protein (1-3) and thrombospondin repeat anonymous protein (TRAP) (4, 5). CS is a constitutive sporozoite surface protein and has a glycophosphatidylinositol anchor. TRAP mediates sporozoite gliding motility and cell invasion in both mosquito and vertebrate hosts (6).TRAP is mobilized from micronemes to the plasma membrane at the apical end of sporozoites, and is translocated to the posterior end during cell migration and invasion (7,8). TRAP spans the plasma membrane, and its cytoplasmic domain connects to the actin cytoskeleton through aldolase, permitting functional cooperation between extracellular adhesive domains and the intracellular actin/myosin motor (8-10). The TRAP ectodomain contains tandem von Willebrand factor A (VWA) and thrombospondin repeat (TSR) domains. A subset of VWA domains, including the inserted (I) domains in integrins, contain metal ion-dependent adhesion sites (MIDAS), with a Mg 2+ ion at the center of the ligand binding site (11). Conformational change transmitted from neighboring domains regulates affinity of I domains for ligand. The TRAP VWA domain contains the sequence signature of a MIDAS. Mutations of putative TRAP VWA domain MIDAS residues and deletion o...

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Section: Resultsmentioning

confidence: 67%

Shape change in the receptor for gliding motility in Plasmodium sporozoites

Song

Koksal

et al. 2012

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

142

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“…[10] We assume that BSA in the medium sticks to the PDMS or activates sporozoites, which can move on a wide variety of substrates. [22][23][24] Sporozoites could associate with pillars in different ways: they could be found on the top ( Figure 1C, top panel), at the side of ( Figure 1C, middle panel) and between pillars ( Figure 1C, bottom panel).…”

Section: Resultsmentioning

confidence: 99%

“…Only few showed a type of motility previously described as patch-gliding, where parasites are attached to the substrate with a single adhesion site and move over this adhesion site back and forth. [22] No change in the capacity of midgut sporozoites to glide was observed in a variety of pillar arrays with different pillar diameters and pillar-to-pillar distances. This suggests that sporozoites do not actively adopt their shape but that the shape is determined during developmental maturation as is their capacity to attach to substrates and perform gliding.…”

Section: Discussionmentioning

confidence: 99%

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Microstructured Blood Vessel Surrogates Reveal Structural Tropism of Motile Malaria Parasites

Muthinja

Ripp

Hellmann

et al. 2017

Adv Healthcare Materials

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Muthinja, M. J. et al. (2017) Microstructured blood vessel surrogates reveal structural tropism of motile malaria parasites. Advanced Healthcare Materials, 6(6), 1601178. (doi:10.1002/adhm.201601178) There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it. This is the peer-reviewed version of the following article: Muthinja, M. J. et al. (2017) Investigating the association of sporozoites to pillars in arrays displaying pillars of different diameters revealed that the crescent-shaped parasites prefer to associate with and migrate around pillars with a similar curvature. This suggests that after transmission by a mosquito malaria parasites might use a structural tropism to recognize blood capillaries in the dermis in order to gain access to the blood stream.4

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“…2E). As a small-molecule tool, ALPin1 may help identify unknown components of the actin-myosin motor-dependent gliding machinery (11,12).…”

mentioning

confidence: 99%

In Vitro Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites

Lentz

Sattler

Fendler

et al. 2015

Antimicrob Agents Chemother

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c wALADin1 benzimidazoles are specific inhibitors of ␦-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 M, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates.

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Plasmodium Sporozoite Motility Is Modulated by the Turnover of Discrete Adhesion Sites

Cited by 166 publications

References 43 publications

Shape change in the receptor for gliding motility in Plasmodium sporozoites

Shape change in the receptor for gliding motility in Plasmodium sporozoites

Microstructured Blood Vessel Surrogates Reveal Structural Tropism of Motile Malaria Parasites

In Vitro Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites

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