Biochemical and biophysical characterisation of DBL1α1-varO, the rosetting domain of PfEMP1 from the VarO line of Plasmodium falciparum

Juillerat, Alexandre; Igonet, Sébastien; Vigan-Womas, Inès; Guillotte, Micheline; Gangnard, Stéphane; Faure, Grazyna; Baron, Bruno; Raynal, Bertrand; Mercereau‐Puijalon, Odile; Bentley, G.A.

doi:10.1016/j.molbiopara.2009.12.008

Cited by 29 publications

(54 citation statements)

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“…We show here that NTS-DBL1α 1 -VarO binds to the RBC surface and that binding can be inhibited with increasing amounts of heparin, mirroring the capacity of this oligosaccharide to disrupt rosettes. These observations, and the efficacy with which domain-specific antibodies disrupt rosettes (7,16), indicate a direct role for NTS-DBL1α 1 in this phenomenon (Fig. 1).…”

Section: Discussionmentioning

confidence: 77%

“…We have shown that heparin disrupts Palo Alto 89F5 VarO rosettes and binds to recombinant NTS-DBL1α 1 -VarO with μM affinity (16). The receptor for VarO rosetting has not yet been identified.…”

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confidence: 96%

“…Studies on laboratory parasite strains have shown that the DBL1α 1 subclass is directly implicated in rosette formation (2, 7). In spite of a diversity of rosetting phenotypes, which interact with a variety of receptors, rosettes are frequently disrupted by sulfated glycosaminoglycans (GAG), such as heparin (6,(12)(13)(14)(15)(16). Heparin efficiently disrupts rosettes but may enhance CD36-dependent adhesion of iRBC to microvascular endothelium cells (17).…”

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confidence: 99%

“…The receptor for VarO rosetting has not yet been identified. Nonetheless, heparin and the chemically related GAG, heparan sulfate, can be excluded as candidates: Heparin is present only in the granules of connective tissue mast cells and heparan sulfate, while being present on the RBC surface and reported as the receptor for one rosetting phenotype (18), disrupts VarO rosettes very weakly (16). The efficacy of VarO rosette disruption by different oligosaccharides is directly correlated with their affinity for recombinant NTS-DBL1α 1 , suggesting that the ligand competes with the rosetting receptor or alters the receptor-binding site.…”

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confidence: 99%

“…Inclusion of NTS was essential for successful expression of DBL1α 1 in soluble form in the Escherichia coli and baculovirus/ insect cell systems (16). Moreover, separation of NTS from the core domain after cleavage at R69 was only achieved under strong denaturing conditions (6M guanidine/HCl, 500 mM NaCl).…”

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confidence: 99%

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Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition

Juillerat

Lewit-Bentley

Guillotte

et al. 2011

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

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The human malaria parasite Plasmodium falciparum can cause infected red blood cells (iRBC) to form rosettes with uninfected RBC, a phenotype associated with severe malaria. Rosetting is mediated by a subset of the Plasmodium falciparum membrane protein 1 (PfEMP1) variant adhesins expressed on the infected host-cell surface. Heparin and other sulfated oligosaccharides, however, can disrupt rosettes, suggesting that therapeutic approaches to this form of severe malaria are feasible. We present a structural and functional study of the N-terminal domain of PfEMP1 from the VarO variant comprising the N-terminal segment (NTS) and the first DBL domain (DBL1α 1 ), which is directly implicated in rosetting. We demonstrate that NTS-DBL1α 1 -VarO binds to RBC and that heparin inhibits this interaction in a dose-dependent manner, thus mimicking heparin-mediated rosette disruption. We have determined the crystal structure of NTS-DBL1α 1 , showing that NTS, previously thought to be a structurally independent component of PfEMP1, forms an integral part of the DBL1α domain. Using mutagenesis and docking studies, we have located the heparin-binding site, which includes NTS. NTS, unique to the DBL α-class domain, is thus an intrinsic structural and functional component of the N-terminal VarO domain. The specific interaction observed with heparin opens the way for developing antirosetting therapeutic strategies. Severe Plasmodium falciparum malaria is frequently associated with infected red blood cells (iRBC) forming rosettes with uninfected RBC (1-3). Although the relationship between rosetting and malaria pathology is not thoroughly understood, enhanced invasion of RBC (4) and microvascular obstruction caused by high rosette densities (5) are probably major contributing factors. Rosetting is mediated by a subset of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesins (2, 6, 7), a protein family involved in falciparum cyto-adhesion. PfEMP1 adhesins are expressed on the surface of the iRBC during the trophozoite and schizont phases and are clustered in knob-like structures, where they interact with diverse host receptors (8).PfEMP1 has a large N-terminal extracellular region comprising an N-terminal segment (NTS), and several Duffy binding-like (DBL) domains and cysteine-rich interdomain regions (CIDR) (8-10). DBL and CIDR domains can be assigned to a small number of sequence classes. The arrangement of these domains is modular, but most variants begin with NTS followed by DBL1α. Indeed, α-class DBL domains occur only at the N-terminal position of PfEMP1 (11). Studies on laboratory parasite strains have shown that the DBL1α 1 subclass is directly implicated in rosette formation (2, 7). In spite of a diversity of rosetting phenotypes, which interact with a variety of receptors, rosettes are frequently disrupted by sulfated glycosaminoglycans (GAG), such as heparin (6,(12)(13)(14)(15)(16). Heparin efficiently disrupts rosettes but may enhance CD36-dependent adhesion of iRBC to microvascular endothelium cells (17). The ...

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Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 96%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition

Juillerat

Lewit-Bentley

Guillotte

et al. 2011

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

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Targeted Drug Delivery for Antimalarial Therapy

Zwayen

Zwain

Singh

2022

Drug Development for Malaria

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Combating malaria with nanotechnology-based targeted and combinatorial drug delivery strategies

Thakkar

Brijesh

2016

Drug Deliv. and Transl. Res.

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Despite the advancement of science, infectious diseases such as malaria remain an ongoing challenge globally. The main reason this disease still remains a menace in many countries around the world is the development of resistance to many of the currently available anti-malarial drugs. While developing new drugs is rather expensive and the prospect of a potent vaccine is still evading our dream of a malaria-free world, one of the feasible options is to package the older drugs in newer ways. For this, nano-sized drug delivery vehicles have been used and are proving to be promising prospects in the way malaria will be treated in the future. Since, monotherapy has given way to combination therapy in malaria treatment, nanotechnology-based delivery carriers enable to encapsulate various drug moieties in the same package, thus avoiding the complications involved in conjugation chemistry to produce hybrid drug molecules. Further, we envisage that using targeted delivery approaches, we may be able to achieve a much better radical cure and curb the side effects associated with the existing drug molecules. Thus, this review will focus on some of the nanotechnology-based combination and targeted therapies and will discuss the possibilities of better therapies that may be developed in the future.

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Biochemical and biophysical characterisation of DBL1α1-varO, the rosetting domain of PfEMP1 from the VarO line of Plasmodium falciparum

Cited by 29 publications

References 42 publications

Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition

Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition

Targeted Drug Delivery for Antimalarial Therapy

Combating malaria with nanotechnology-based targeted and combinatorial drug delivery strategies

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