Conformational dynamics and antigenicity in the disordered malaria antigen merozoite surface protein 2. 2015

Christopher A MacRaild, and Milan Zachrdla, and Dean Andrew, and Bankala Krishnarjuna, and Jiří Nováček, and Lukáš Žídek, and Vladimír Sklenář, and Jack S Richards, and James G Beeson, and Robin F Anders, and Raymond S Norton
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052, Australia.

Merozoite surface protein 2 (MSP2) of Plasmodium falciparum is an abundant, intrinsically disordered protein that is GPI-anchored to the surface of the invasive blood stage of the malaria parasite. Recombinant MSP2 has been trialled as a component of a malaria vaccine, and is one of several disordered proteins that are candidates for inclusion in vaccines for malaria and other diseases. Nonetheless, little is known about the implications of protein disorder for the development of an effective antibody response. We have therefore undertaken a detailed analysis of the conformational dynamics of the two allelic forms of MSP2 (3D7 and FC27) using NMR spectroscopy. Chemical shifts and NMR relaxation data indicate that conformational and dynamic properties of the N- and C-terminal conserved regions in the two forms of MSP2 are essentially identical, but significant variation exists between and within the central variable regions. We observe a strong relationship between the conformational dynamics and the antigenicity of MSP2, as assessed with antisera to recombinant MSP2. Regions of increased conformational order in MSP2, including those in the conserved regions, are more strongly antigenic, while the most flexible regions are minimally antigenic. This suggests that modifications that increase conformational order may offer a means to tune the antigenicity of MSP2 and other disordered antigens, with implications for vaccine design.

UI MeSH Term Description Entries
D010963 Plasmodium falciparum A species of protozoa that is the causal agent of falciparum malaria (MALARIA, FALCIPARUM). It is most prevalent in the tropics and subtropics. Plasmodium falciparums,falciparums, Plasmodium
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D000953 Antigens, Protozoan Any part or derivative of any protozoan that elicits immunity; malaria (Plasmodium) and trypanosome antigens are presently the most frequently encountered. Protozoan Antigens
D015800 Protozoan Proteins Proteins found in any species of protozoan. Proteins, Protozoan
D019906 Nuclear Magnetic Resonance, Biomolecular NMR spectroscopy on small- to medium-size biological macromolecules. This is often used for structural investigation of proteins and nucleic acids, and often involves more than one isotope. Biomolecular Nuclear Magnetic Resonance,Heteronuclear Nuclear Magnetic Resonance,NMR Spectroscopy, Protein,NMR, Biomolecular,NMR, Heteronuclear,NMR, Multinuclear,Nuclear Magnetic Resonance, Heteronuclear,Protein NMR Spectroscopy,Biomolecular NMR,Heteronuclear NMR,Multinuclear NMR,NMR Spectroscopies, Protein,Protein NMR Spectroscopies,Spectroscopies, Protein NMR,Spectroscopy, Protein NMR

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