The Repeat Region of the Circumsporozoite Protein is Critical for Sporozoite Formation and Maturation in Plasmodium

Ferguson, David J. P.; Balaban, Amanda E.; Patzewitz, Eva Maria; Wall, Richard J.; Hopp, Christine S.; Poulin, Benoit; Mohmmed, Asif; Malhotra, Pawan; Coppi, Alida; Sinnis, Photini; Tewari, Rita

doi:10.1371/journal.pone.0113923

Cited by 43 publications

(63 citation statements)

References 34 publications

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“…Ultrastructure analysis of oocyst development revealed an enlarged nucleus that formed a large multiple lobed structure with multiple nuclear poles, followed by formation of large numbers of sporozoites at the plasmalemma of the oocyst (Fig. 5Bi), as described previously (Ferguson et al, 2014;Schrevel et al, 1977). Detailed examination showed nuclear poles with kinetochores directed toward the developing sporozoites ( Fig.…”

Section: Rapid Spindle Dynamics and Ndc80-gfp Localisation During Endsupporting

confidence: 66%

Real-time dynamics of Plasmodium NDC80 reveals unusual modes of chromosome segregation during parasite proliferation

Pandey

Zeeshan

Ferguson

et al. 2019

Preprint

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Eukaryotic cell proliferation requires chromosome replication and precise segregation, followed by cell division, to ensure daughter cells have identical genomic copies. The kinetochore is a multi-protein structure assembled on chromosome centromeres, which mediates attachment to spindle microtubules and chromosome segregation during mitosis. Plasmodium spp., the causative agent of malaria, undergoes closed mitosis with an intact nuclear membrane and intranuclear mitotic spindle. However, the regulation of the main events of mitosis and meiosis, including chromosome segregation, is poorly understood in this parasite. In part this is due to a distinct lack of markers for tracking kinetochore dynamics. Since NDC80 is the conserved component of the kinetochore complex, we labelled NDC80 with either a C-terminal GFP or mCherry tag by recombination at the endogenous locus to generate transgenic lines of the rodent malaria parasite Plasmodium berghei. We show that NDC80 is located at a single cluster of all kinetochores and examine its spatio-temporal dynamics throughout all proliferative stages of the parasite life cycle.We also compare the location of NDC80 with that of the kinetochore using electron microscopy. These transgenic parasite lines are a very useful resource to identify and study the kinetochore complex and follow chromosome dynamics during malaria parasite development.

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Section: Rapid Spindle Dynamics and Ndc80-gfp Localisation During Endsupporting

confidence: 66%

Real-time dynamics of Plasmodium NDC80 reveals unusual modes of chromosome segregation during parasite proliferation

Pandey

Zeeshan

Ferguson

et al. 2019

Preprint

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“…However, removal of the repetitive regions of other proteins can affect activity; deletion of repeat regions of the parasite circumsporozoite protein and ring-exported protein 1 (REX1) lead to loss of protein function (36, 37). The knob-associated histidine-rich protein (KAHRP) is involved in both rigidifying the host cell (23) and the formation of cytoadherent knob structures (16), and deletion of a C-terminal sequence encompassing two lysine-rich repetitive sequences results in smaller knob structures and reduced cytoadhesion (38).…”

Section: Introductionmentioning

confidence: 99%

Expansion of Lysine-rich Repeats in Plasmodium Proteins Generates Novel Localization Sequences That Target the Periphery of the Host Erythrocyte

Davies

Thalassinos

Osborne

2016

Journal of Biological Chemistry

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Repetitive low complexity sequences, mostly assumed to have no function, are common in proteins that are exported by the malaria parasite into its host erythrocyte. We identify a group of exported proteins containing short lysine-rich tandemly repeated sequences that are sufficient to localize to the erythrocyte periphery, where key virulence-related modifications to the plasma membrane and the underlying cytoskeleton are known to occur. Efficiency of targeting is dependent on repeat number, indicating that novel targeting modules could evolve by expansion of short lysine-rich sequences. Indeed, analysis of fragments of GARP from different species shows that two novel targeting sequences have arisen via the process of repeat expansion in this protein. In the protein Hyp12, the targeting function of a lysine-rich sequence is masked by a neighboring repetitive acidic sequence, further highlighting the importance of repetitive low complexity sequences. We show that sequences capable of targeting the erythrocyte periphery are present in at least nine proteins from Plasmodium falciparum and one from Plasmodium knowlesi. We find these sequences in proteins known to be involved in erythrocyte rigidification and cytoadhesion as well as in previously uncharacterized exported proteins. Together, these data suggest that expansion and contraction of lysine-rich repeats could generate targeting sequences de novo as well as modulate protein targeting efficiency and function in response to selective pressure.

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“…Gene knock-out studies in P. falciparum have demonstrated that CSP is required for the structural development of sporozoites (16). A recent study demonstrated that the repeat region is also critically required for sporozoite formation and maturation (17). Other than the structural requirement of CSP for sporozoites, in the human host, it is functionally involved in hepatocyte invasion by the parasite, as antibodies directed against CSP prevented sporozoite invasion into hepatocytes (18 -20).…”

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Force Spectroscopy of the Plasmodium falciparum Vaccine Candidate Circumsporozoite Protein Suggests a Mechanically Pliable Repeat Region

Patra

Sharma

Ainavarapu

2017

Journal of Biological Chemistry

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The most effective vaccine candidate of malaria is based on the circumsporozoite protein (CSP), a major surface protein implicated in the structural strength, motility, and immune evasion properties of the infective sporozoites. It is suspected that reversible conformational changes of CSP are required for infection of the mammalian host, but the detailed structure and dynamic properties of CSP remain incompletely understood, limiting our understanding of its function in the infection. Here, we report the structural and mechanical properties of the CSP studied using single-molecule force spectroscopy on several constructs, one including the central region of CSP, which is rich in NANP amino acid repeats (CSP), and a second consisting of a near full-length sequence without the signal and anchor hydrophobic domains (CSP). Our results show that the CSP is heterogeneous, with 40% of molecules requiring virtually no mechanical force to unfold (<10 piconewtons (pN)), suggesting that these molecules are mechanically compliant and perhaps act as entropic springs, whereas the remaining 60% are partially structured with low mechanical resistance (∼70 pN). CSP having multiple force peaks suggests specifically folded domains, with two major populations possibly indicating the open and collapsed forms. Our findings suggest that the overall low mechanical resistance of the repeat region, exposed on the outer surface of the sporozoites, combined with the flexible full-length conformations of CSP, may provide the sporozoites not only with immune evasion properties, but also with lubricating capacity required during its navigation through the mosquito and vertebrate host tissues. We anticipate that these findings would further assist in the design and development of future malarial vaccines.

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The Repeat Region of the Circumsporozoite Protein is Critical for Sporozoite Formation and Maturation in Plasmodium

Cited by 43 publications

References 34 publications

Real-time dynamics of Plasmodium NDC80 reveals unusual modes of chromosome segregation during parasite proliferation

Real-time dynamics of Plasmodium NDC80 reveals unusual modes of chromosome segregation during parasite proliferation

Expansion of Lysine-rich Repeats in Plasmodium Proteins Generates Novel Localization Sequences That Target the Periphery of the Host Erythrocyte

Force Spectroscopy of the Plasmodium falciparum Vaccine Candidate Circumsporozoite Protein Suggests a Mechanically Pliable Repeat Region

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