Genetic structure of two erythrocyte binding antigens of Plasmodium falciparum reveals a contrasting pattern of selection

Chowdhury, Pramita; Sen, Siddhartha; Kanjilal, Sumana Datta; Sengupta, Sanghamitra

doi:10.1016/j.meegid.2017.11.006

Cited by 9 publications

(3 citation statements)

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“…Inclusion of the geographically predominant version of epitopes is another essential criterion. Due to extensive polymorphic nature of merozoite proteins such as AMA-1 and MSP-1, focus has currently been shifted to PfRH antigens [ 27 , 49 , 50 ]. Since, India serves as a large and diverse reservoir of P. falciparum parasites, the level and pattern of genetic variability of Pfrh family of ligands, which take important part in host-parasite interaction during erythrocyte invasion by P. falciparum , are thoroughly investigated.…”

Section: Discussionmentioning

confidence: 99%

Population genetic and biophysical evidences reveal that purifying selection shapes the genetic landscape of Plasmodium falciparum RH ligands in Chhattisgarh and West Bengal, India

Ghoshal

Chowdhury

Ray

et al. 2020

Malar J

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Background Reticulocyte binding protein-like homologs (RHs) are currently being evaluated as anti-erythrocytic stage vaccine targets against Plasmodium falciparum malaria. Present study explores the possible evolutionary drivers shaping the genetic organization of Pfrhs in Indian parasite population. It simultaneously evaluates a putative gain-of-function variant of PfRH5, a keystone member of PfRH family. Methods Receptor binding regions of Pfrh1, Pfrh2a/b, Pfrh4 and whole Pfrh5 were amplified using blood samples of P. falciparum malaria patients from Chhattisgarh and West Bengal and sequenced. Assembled sequences were analysed using MEGA7 and DnaSPv6. Binding affinities of recombinant PfRH5 proteins with basigin (BSG) were compared using in silico (CHARMM and AUTODOCK) and in vitro (Circular dichroism, fluorescence spectroscopy and isothermal titration calorimetry) methods. Results Pfrh1 (0.5), Pfrh2a/b (0.875), Pfrh4 (0.667) and Pfrh5 (0.778) sequence changes corresponded to low frequency (< 0.05) variants which resulted in an overall negative Tajima’s D. Since mismatch distribution of none of the Pfrh loci corroborated with the model of demographic expansion, a possible role of natural selection formulating Pfrh sequence diversity was investigated. Among the 5 members, Pfrh5 displayed very high dN/dS (5.7) ratio. Nevertheless, the model of selective sweep due to presence of any advantageous substitutions could not be invoked as polymorphic nonsynonymous sites (17/18) for Pfrh5 exceeded significantly over the divergent (62/86) ones (p = 0.0436). The majority of extant PfRH5 sequences (52/83) differed from the reference Pf3D7 allele by a single amino acid mismatch (C203Y). This non-conservative alteration was predicted to lower the total interaction energy of that PfRH5variant with BSG, compared to PfRH53D7. Biophysical evidences validated the proposition that PfRH5variant formed a more stable complex with BSG. Thermodynamic association constant for interaction of BSG with PfRH5variant was also found to be higher (Kavariant = 3.63E6 ± 2.02E6 M−1 and Ka3D7 = 1.31E6 ± 1.21E6 M−1). Conclusions Together, the study indicates that the genetic architecture of Pfrhs is principally shaped by purifying selection. The most abundant and ubiquitous PfRH5 variant harbouring 203Y, exhibits a greater affinity for BSG compared to PfRH53D7 possessing 203C allele. The study underscores the importance of selecting the functional allele that best represents circulating strains in natural parasite populations as vaccine targets.

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Section: Discussionmentioning

confidence: 99%

Population genetic and biophysical evidences reveal that purifying selection shapes the genetic landscape of Plasmodium falciparum RH ligands in Chhattisgarh and West Bengal, India

Ghoshal

Chowdhury

Ray

et al. 2020

Malar J

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“…1 ). These EBAs bind to terminal sialic acid (Neu5Ac) of glycophorins A and C on the surface of human erythrocytes using a “CRD Repeats” arrangement ( Chowdhury et al. 2018 ).…”

Section: Classification Of Tandem-repeat Lectinsmentioning

confidence: 99%

Tandem-repeat lectins: structural and functional insights

Olvera-Lucio,

Riveros-Rosas,

Quintero-Martínez

et al. 2024

Glycobiology

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Multivalency in lectins plays a pivotal role in influencing glycan cross-linking, thereby affecting lectin functionality. This multivalency can be achieved through oligomerization, the presence of tandemly repeated carbohydrate recognition domains, or a combination of both. Unlike lectins that rely on multiple factors for the oligomerization of identical monomers, tandem-repeat lectins inherently possess multivalency, independent of this complex process. The repeat domains, although not identical, display slightly distinct specificities within a predetermined geometry, enhancing specificity, affinity, avidity and even oligomerization. Despite the recognition of this structural characteristic in recently discovered lectins by numerous studies, a unified criterion to define tandem-repeat lectins is still necessary. We suggest defining them multivalent lectins with intrachain tandem repeats corresponding to carbohydrate recognition domains, independent of oligomerization. This systematic review examines the folding and phyletic diversity of tandem-repeat lectins and refers to relevant literature. Our study categorizes all lectins with tandemly repeated carbohydrate recognition domains into nine distinct folding classes associated with specific biological functions. Our findings provide a comprehensive description and analysis of tandem-repeat lectins in terms of their functions and structural features. Our exploration of phyletic and functional diversity has revealed previously undocumented tandem-repeat lectins. We propose research directions aimed at enhancing our understanding of the origins of tandem-repeat lectin and fostering the development of medical and biotechnological applications, notably in the design of artificial sugars and neolectins.

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“…Plasmodium falciparum EBA-175 ligand [29–32] was the first and is the best characterized protein of the EBL family, considered to be one of the most important P. falciparum merozoite invasion ligands [32, 33]. It has been shown that EBA-175 is a target of human inhibitory antibodies present in sera of malarial patients, while animal antibodies recognizing EBA-175 can block merozoite invasion of RBCs [34–36].…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte glycophorins as receptors for Plasmodium merozoites

et al. 2019

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Glycophorins are heavily glycosylated sialoglycoproteins of human and animal erythrocytes. In humans, there are four glycophorins: A, B, C and D. Glycophorins play an important role in the invasion of red blood cells (RBCs) by malaria parasites, which involves several ligands binding to RBC receptors. Four Plasmodium falciparum merozoite EBL ligands have been identified: erythrocyte-binding antigen-175 (EBA-175), erythrocyte-binding antigen-181 (EBA-181), erythrocyte-binding ligand-1 (EBL-1) and erythrocyte-binding antigen-140 (EBA-140). It is generally accepted that glycophorin A (GPA) is the receptor for P. falciparum EBA-175 ligand. It has been shown that α(2,3) sialic acid residues of GPA O-glycans form conformation-dependent clusters on GPA polypeptide chain which facilitate binding. P. falciparum can also invade erythrocytes using glycophorin B (GPB), which is structurally similar to GPA. It has been shown that P. falciparum EBL-1 ligand binds to GPB. Interestingly, a hybrid GPB-GPA molecule called Dantu is associated with a reduced risk of severe malaria and ameliorates malaria-related morbidity. Glycophorin C (GPC) is a receptor for P. falciparum EBA-140 ligand. Likewise, successful binding of EBA-140 depends on sialic acid residues of N- and O-linked oligosaccharides of GPC, which form a cluster or a conformational structure depending on the presence of peptide fragment encompassing amino acids (aa) 36–63. Evaluation of the homologous P. reichenowi EBA-140 unexpectedly revealed that the chimpanzee homolog of human glycophorin D (GPD) is probably the receptor for this ligand. In this review, we concentrate on the role of glycophorins as erythrocyte receptors for Plasmodium parasites. The presented data support the long-lasting idea of high evolutionary pressure exerted by Plasmodium on the human glycophorins, which emerge as important receptors for these parasites.

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Genetic structure of two erythrocyte binding antigens of Plasmodium falciparum reveals a contrasting pattern of selection

Cited by 9 publications

References 45 publications

Population genetic and biophysical evidences reveal that purifying selection shapes the genetic landscape of Plasmodium falciparum RH ligands in Chhattisgarh and West Bengal, India

Population genetic and biophysical evidences reveal that purifying selection shapes the genetic landscape of Plasmodium falciparum RH ligands in Chhattisgarh and West Bengal, India

Tandem-repeat lectins: structural and functional insights

Erythrocyte glycophorins as receptors for Plasmodium merozoites

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