Non-synonymous amino acid alterations in PfEBA-175 modulate the merozoite ligand's ability to interact with host's Glycophorin A receptor

Autor: Sanhita Ray, Srikanta Sen, Anjan Kr. Dasgupta, Pramita Chowdhury, Ayan Chakraborty, Sanghamitra Sengupta
Rok vydání: 2020
Předmět:
0301 basic medicine
Microbiology (medical)
Circular dichroism
Protein Folding
Erythrocytes
030106 microbiology
Population
Plasmodium falciparum
Protozoan Proteins
Artesunate
Microbiology
Host-Parasite Interactions
03 medical and health sciences
chemistry.chemical_compound
Antimalarials
Protein Domains
Genetics
Glycophorin
Animals
Humans
Glycophorins
Malaria
Falciparum
Receptor
education
Molecular Biology
Ecology
Evolution
Behavior and Systematics
chemistry.chemical_classification
education.field_of_study
Polymorphism
Genetic
biology
Ligand
Intracellular Signaling Peptides and Proteins
biology.organism_classification
Artemisinins
Recombinant Proteins
Amino acid
Molecular Docking Simulation
030104 developmental biology
Infectious Diseases
chemistry
Biochemistry
Amino Acid Substitution
biology.protein
Protein Binding
Zdroj: Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 85
ISSN: 1567-7257
Popis: The pathological outcome of malaria due to Plasmodium falciparum infection depends largely on erythrocyte invasion by blood-stage merozoites which employ a cascade of interactions occurring between parasite ligands and RBC receptors. In a previous study exploring the genetic diversity of region-II of PfEBA-175, a ligand that plays a crucial part in parasite's RBC entry through Glycophorin A (GPA) receptor, we demonstrated that F2 domain of region-II underwent positive selection in Indian P. falciparum population through the accumulation of non-synonymous polymorphisms. Here, we examine the functional impact of two highly prevalent non-synonymous alterations in F2, namely Q584E & E592A, using a battery of molecular, biophysical and in-silico techniques. Application of circular dichroism, FTIR, fluorescence spectroscopy reveals that secondary and three-dimensional folding of recombinant-F2 protein carrying 584E and 592A residues (F2-Mut) differs significantly from that carrying 584Q and 592E (F2-3D7). A comparison of spectroscopic and thermodynamic parameters shows that F2-Mut is capable of forming a complex with GPA with higher efficiency compared to F2-3D7. In silico docking predicts both artemisinin and artesunate possess the capacity of slipping into the GPA binding crevices of PfEBA-175 and disrupt PfEBA-GPA association. However, the estimated affinity of artesunate towards PfEBA-175 with 584E and 592A residues is higher than that of artemisinin. Thermodynamic parameters computed using isotherms are concordant with this in-silico prediction. Together, our data suggest that the presence of amino acid alterations in F2 provide structural and functional stability favoring PfEBA-GPA interaction and artesunate can efficiently disrupt the interaction between GPA and PfEBA-175 even carrying altered amino acid residues. The present study alerts the malaria research community by presenting evidence that the parasite is gaining evolutionary fitness by cultivating genetic alterations in many of its proteins.
Databáze: OpenAIRE
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