Receptor-binding residues lie in central regions of Duffy-binding–like domains involved in red cell invasion and cytoadherence by malaria parasites

Mayor, Alfredo; Bir, Nivedita; Sawhney, Ritica; Singh, Shailja; Pattnaik, Priyabrata; Singh, Saurabh Kumar; Sharma, Amit; Chitnis, Chetan E.

doi:10.1182/blood-2004-05-1722

Cited by 41 publications

(39 citation statements)

References 30 publications

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“…Recent studies have shown that the receptor-binding residues of DBL1␣ lie in the central parts of the domain (9). Parallel experiments with other DBL orthologs have also identified receptor affinity in this region (28,29), indicating the importance of this domain in binding to host receptors.…”

Section: D Model Constructionmentioning

confidence: 76%

“…These ␣-helical regions probably have morphological constraints but are likely to be exposed to the immune system and possibly available to function as adhesins. Furthermore, the location of the degenerate motifs in DBL1␣ correspond to the regions of fold-conservation and receptor-interaction in the DBL domains of EBA-175 and Pk␣-DBL, suggesting that PfEMP1-DBL1␣ has retained a similar conserved structure and area for receptor binding (9). However, it has to be stressed that, although DBL1␣ is a hypervariable protein domain, it contains regions with high conservation.…”

Section: Discussionmentioning

confidence: 99%

“…The Duffy binding-like domain-␣ (DBL1␣) located in the Nterminal head structure of PfEMP1 mediates rosetting and endothelial binding of IE. These binding processes occur by means of a range of different receptors, including heparan sulfate, complement receptor 1, and/or the blood group A antigen (6)(7)(8)(9). Rosetting and endothelial binding are intimately associated with severe falciparum malaria (10)(11)(12)(13)(14).…”

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confidence: 99%

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PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

Normark

Nilsson

Ribacke

et al. 2007

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

110

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An infection with Plasmodium falciparum may lead to severe malaria as a result of excessive binding of infected erythrocytes in the microvasculature. Vascular adhesion is mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP1), which is encoded for by highly polymorphic members of the var-gene family. Here, we profile var gene transcription in fresh P. falciparum trophozoites from Ugandan children with malaria through var-specific DBL1␣-PCR amplification and sequencing. A method for subsectioning region alignments into homology areas (MOTIFF) was developed to examine collected sequences. Specific PfEMP1-DBL1␣ amino acid motifs correlated with rosetting and severe malaria, with motif location corresponding to distinct regions of receptor interaction. The method is potentially applicable to other families of variant proteins and may be useful in identifying sequencephenotype relationships. The results suggest that certain PfEMP1 sequences are predisposed to inducing severe malaria.homology areas ͉ antigenic variation ͉ rosetting P lasmodium falciparum malaria infection is one of the primary contributors to childhood mortality in many developing countries. Despite exhaustive research efforts, no vaccine capable of conferring an adequate level of immunity has been developed to date. Vaccine development is encouraged by the fact that children attain conditional immunity to severe malaria after relatively few infections. However, a lack of insight into the molecular interplay between the parasite and the host continues to thwart efforts at vaccine development. One of the key factors in this process is the ability of the parasite to continually express a plethora of antigenic variants of gene families, whose selection appears to correspond with interactions with the host immune system.Severe malaria, a highly lethal form of the disease, is, in part, attributable to the sequestration of P. falciparum-infected erythrocytes (IE) and uninfected erythrocytes in postcapillary venules of the brain, the lungs, or other organs (1). P. falciparum expresses a number of proteins at the erythrocyte surface that are closely involved in the excessive sequestration characteristic of severe malaria. The polypeptide most closely scrutinized to date, PfEMP1, is a large 200-to 400-kDa clonally variant antigen encoded by a repertoire of Ϸ60 var genes (2). The var genes present a two-exon structure encoding a conserved C terminus that contains a predicted transmembrane region and a polymorphic submodular N terminus. This N terminus region possesses a number of cysteine-rich domains that are intimately involved in the sequestration of the parasite in the microvasculature (3-5). The Duffy binding-like domain-␣ (DBL1␣) located in the Nterminal head structure of PfEMP1 mediates rosetting and endothelial binding of IE. These binding processes occur by means of a range of different receptors, including heparan sulfate, complement receptor 1, and/or the blood group A antigen (6-9). Rosetting and endothelial binding are intimately associa...

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Section: D Model Constructionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

Normark

Nilsson

Ribacke

et al. 2007

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

110

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“…The binding site of the R29 var1-encoded DBL␣ domain has been mapped to the central region including amino acids 133 to 366 (Cys residues 5 to 12) (20). A DNA fragment (nucleotides 399 to 1098) encoding R29 DBL␣ (20,31) fused to a hexahistidine tag at the C-terminal end was amplified by a PCR using primers 5Ј-GCA TGC CAT GGA TAG AAA TTT AGA ATA TTT GAT C-3Ј and 5Ј-CGA GTG TCG ACT CAG TGA TGG TGA TGG TGA TGA CGT GGA CAA TTT AAA TCT ATA AAG-3Ј, with a plasmid containing a DNA fragment encoding DBL␣ of P. falciparum R29 as the template.…”

Section: Expression Of Rdbl␣mentioning

confidence: 99%

“…The DBL␣ domain encoded by R29 var1, the var gene expressed by the rosetting parasite R29, binds complement receptor 1 (CR1) on erythrocytes to mediate the formation of rosettes (31). The CR1 binding residues map to the 233-aminoacid central stretch of the DBL␣ domain (20).…”

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confidence: 99%

Functional and Immunological Characterization of a Duffy Binding-Like Alpha Domain from Plasmodium falciparum Erythrocyte Membrane Protein 1 That Mediates Rosetting

et al. 2009

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The Duffy binding-like (DBL) domains are common adhesion modules present in Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants, which are responsible for immune evasion and cytoadherence. Knowledge about how immune responses are acquired against polymorphic DBL domains of PfEMP1 can aid in the development of vaccines for malaria. A recombinant DBL␣ domain, encoded by R29 var1, which binds complement receptor 1 to mediate rosetting by the P. falciparum laboratory strain R29, was expressed in Escherichia coli, renatured by oxidative refolding to its native form, and purified to homogeneity. Antibody levels in 704 plasmas obtained from residents of areas of different levels of malaria endemicity in Orissa (India) and Manhiça (Mozambique) were assessed by enzyme-linked immunosorbent assay. The refolded DBL␣ domain was pure, homogeneous, and functional in that it bound human erythrocytes with specificity and was capable of inhibiting rosetting. The proportion of individuals who had measurable anti-DBL␣ immunoglobulin G responses was low in areas of low malaria endemicity in Orissa (6.7%) but high in areas of high endemicity in Orissa (87.5%) and Manhiça (74.5%). Seroprevalence and antibody levels against the recombinant protein increased with the age of inhabitants from areas with high transmission rates (P < 0.001). Half of the children in these areas had seroconverted by the age of 5 years. These findings suggest that in spite of the extreme polymorphism of PfEMP1 DBL␣ domains, the acquisition of specific antibodies is rapid and age related and reflects the reduced risk of malaria in areas with high transmission rates. Further studies are required to elucidate the role of these antibodies in protection from malaria.

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A model of the complex between the PfEMP1 malaria protein and the human ICAM‐1 receptor

Bertonati

Tramontano

2007

Proteins

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Malaria is caused by protozoan parasites of the genus Plasmodium. Four species of Plasmodium can infect humans: P. falciparum, P. malariae, P. vivax, and P. ovale. P. falciparum is the only able to cytoadhere to the surface of postcapillary endothelial cells. A key role in cytoadherence is played by the interaction between the PfEMP1 P. falciparum protein and the human intracellular adhesion molecule (ICAM-1) although very little is known about the molecular details of this complex. Here we propose a model for this interaction on the basis of a homology model of the functional domain of PfEMP1 and of the ICAM-1 three dimensional structures. Our model is consistent with the results of many experimental observations, provides a rational explanation for the different binding abilities of different strains of P. falciparum and explains the reduced binding affinity of the A4 strain of P. falciparum for the ICAM-1(Kilifi) polymorphism. On the basis of our model, we can also explain why the murine ICAM-1, although sharing 70% sequence similarity with its human homologue, does not bind PfEMP1, and why the binding of fibrinogen and PfEMP1 to ICAM-1 is mutually exclusive. The model of the complex proposed here can serve as a useful tool for the design and interpretation of biochemical and immunological experimental results.

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Receptor-binding residues lie in central regions of Duffy-binding–like domains involved in red cell invasion and cytoadherence by malaria parasites

Cited by 41 publications

References 30 publications

PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

Functional and Immunological Characterization of a Duffy Binding-Like Alpha Domain from Plasmodium falciparum Erythrocyte Membrane Protein 1 That Mediates Rosetting

A model of the complex between the PfEMP1 malaria protein and the human ICAM‐1 receptor

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