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Imperfect duplicate insertions type of mutations in plasmepsin V modulates binding properties of PEXEL motifs of export proteins in Indian Plasmodium vivax.

ABSTRACT: INTRODUCTION: Plasmepsin V (PM-V) have functionally conserved orthologues across the Plasmodium genus who's binding and antigenic processing at the PEXEL motifs for export about 200-300 essential proteins is important for the virulence and viability of the causative Plasmodium species. This study was undertaken to determine P. vivax plasmepsin V Ind (PvPM-V-Ind) PEXEL motif export pathway for pathogenicity-related proteins/antigens export thereby altering plasmodium exportome during erythrocytic stages. METHOD: We identify and characterize Plasmodium vivax plasmepsin-V-Ind (mutant) gene by cloning, sequence analysis, in silico bioinformatic protocols and structural modeling predictions based on docking studies on binding capacity with PEXEL motifs processing in terms of binding and accessibility of export proteins. RESULTS: Cloning and sequence analysis for genetic diversity demonstrates PvPM-V-Ind (mutant) gene is highly conserved among all isolates from different geographical regions of India. Imperfect duplicate insertion types of mutations (SVSE from 246-249 AA and SLSE from 266-269 AA) were identified among all Indian isolates in comparison to P.vivax Sal-1 (PvPM-V-Sal 1) isolate. In silico bioinformatics interaction studies of PEXEL peptide and active enzyme reveal that PvPM-V-Ind (mutant) is only active in endoplasmic reticulum lumen and membrane embedding is essential for activation of plasmepsin V. Structural modeling predictions based on docking studies with PEXEL motif show significant variation in substrate protein binding of these imperfect mutations with data mined PEXEL sequences. The predicted variation in the docking score and interacting amino acids of PvPM-V-Ind (mutant) proteins with PEXEL and lopinavir suggests a modulation in the activity of PvPM-V in terms of binding and accessibility at these sites. CONCLUSION/SIGNIFICANCE: Our functional modeled validation of PvPM-V-Ind (mutant) imperfect duplicate insertions with data mined PEXEL sequences leading to altered binding and substrate accessibility of the enzyme makes it a plausible target to investigate export mechanisms for in silico virtual screening and novel pharmacophore designing.

SUBMITTER: Rawat M

PROVIDER: S-EPMC3612065 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Imperfect duplicate insertions type of mutations in plasmepsin V modulates binding properties of PEXEL motifs of export proteins in Indian Plasmodium vivax.

Rawat Manmeet M Vijay Sonam S Gupta Yash Y Tiwari Pramod Kumar PK Sharma Arun A

PloS one 20130329 3

<h4>Introduction</h4>Plasmepsin V (PM-V) have functionally conserved orthologues across the Plasmodium genus who's binding and antigenic processing at the PEXEL motifs for export about 200-300 essential proteins is important for the virulence and viability of the causative Plasmodium species. This study was undertaken to determine P. vivax plasmepsin V Ind (PvPM-V-Ind) PEXEL motif export pathway for pathogenicity-related proteins/antigens export thereby altering plasmodium exportome during eryth ...[more]

PMID: 23555891

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Project description:Plasmodium vivax is the most widely distributed human malaria parasite and accounts for approximately the same number of malaria cases as Plasmodium falciparum in India. Compared with P. falciparum, P. vivax is difficult to eradicate because of its tendency to cause relapses, which impacts treatment and control strategies. The genetic diversity of these parasites, particularly of the merozoite surface protein-3 alpha (msp-3?) gene, can be used to help develop a potential vaccine. The present study aimed to investigate the genetic diversity of P. vivax using the highly polymorphic antigen gene msp-3? and to assess the suitability of using this gene for population genetic studies of P. vivax isolates and was carried out in 2004-06. No recent study has been reported for MSP 3? in the recent decade in India. Limited reports are available on the genetic diversity of the P. vivax population in India; hence, this report aimed to improve the understanding of the molecular epidemiology of the parasite by studying the P. vivax msp-3? (Pvmsp-3?) marker from P. vivax field isolates from India.Field isolates were collected from different sites distributed across eight states in India. A total of 182 blood samples were analysed by a nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique using the HhaI and AluI restriction enzymes to determine genetic msp-3? variation among clinical P. vivax isolates.Based on the length variants of the PCR products of Pvmsp-3? gene, three allele sizes, Type A (1.8 kb), Type B (1.5 kb) and Type C (1.2 kb) were detected among the 182 samples. Type A PCR amplicon was more predominant (75.4 %) in the samples compared with the Type B (14.3 %) and Type C (10.0 %) polymorphisms. Among all of the samples analysed, 8.2 % were mixed infections detected by PCR alone. Restriction fragment length polymorphism (RFLP) analysis involving the restriction enzymes AluI and HhaI generated fragment sizes that were highly polymorphic and revealed substantial diversity at the nucleotide level.The present study is the first extensive study in India using the Pvmsp-3? marker. The results indicated that Pvmps-3?, a polymorphic genetic marker of P. vivax, exhibited considerable variability in infection prevalence in field isolates from India. Additionally, the mean multiplicity of infection observed at all of the study sites indicated that P. vivax is highly diverse in nature in India, and Pvmsp-3? is likely an effective and promising epidemiological marker.

Project description:BackgroundGenetic polymorphism is an inevitable component of a multistage infectious organism, such as the malaria parasite. By means of genetic polymorphism, parasite opts particular polymorph and reveals survival advantage. Pvs25 and pvs28 are sexual stage antigen genes, expressed at the ookinete stage inside the mosquito gut, and considered as potential transmission-blocking vaccine candidates. This study presents sequence variations in two important transmission blocking antigen genes pvs25 and pvs28 in the field isolates of P. vivax from the Indian subcontinent.MethodsOne hundred microscopically diagnosed P. vivax isolates were collected from five geographical regions of India. Pvs25 and pvs28 genes were PCR amplified and sequenced to assess sequence variation among field isolates.ResultsA total of 26 amino acid substitutions were observed in Pvs25 (10) and Pvs28 (16) among field isolates of P. vivax. Tandem repeat polymorphism observed in pvs28 shows 3-6 tandem repeats in the field isolates. Seven and eight novel amino acid substitutions were observed in Pvs25 and Pvs28, respectively in Indian isolates. Comparison of amino acid substitutions suggests that majority of substitutions observed in global isolates were also present in Indian subcontinent. A single haplotype was observed to be major haplotype among isolates of Delhi, Nadiad, Chennai and Panna except in isolates of Kamrup. Further, population comparison analyses suggest that P. vivax isolates inhabiting in north-eastern region (Kamrup) were distantly related with the isolates from remaining parts of the country. Majority of the amino acid substitutions observed in Indian isolates were more identical to the substitutions reported from isolates of Thailand and Bangladesh.ConclusionStudy uncovered many new amino acid substitutions as well as a predominance of single haplotype in Indian subcontinent except in north-eastern region of the country. The amino acid substitutions data generated in this study from different geographical regions of the Indian subcontinent could be helpful in designing a more effective anti-malarial transmission-blocking vaccine.

Dataset Information

Imperfect duplicate insertions type of mutations in plasmepsin V modulates binding properties of PEXEL motifs of export proteins in Indian Plasmodium vivax.

Publications

Imperfect duplicate insertions type of mutations in plasmepsin V modulates binding properties of PEXEL motifs of export proteins in Indian Plasmodium vivax.

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