Conformational dynamics and antigenicity in the disordered malaria antigen merozoite surface protein 2.
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.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052, Australia.
Christopher A
CA
MacRaild
NCBR, Faculty of Science, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic; CEITEC, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic.
Milan
M
Zachrdla
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, 3004, Australia.
Dean
D
Andrew
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052, Australia.
Bankala
B
Krishnarjuna
NCBR, Faculty of Science, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic; CEITEC, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic.
Jiří
J
Nováček
NCBR, Faculty of Science, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic; CEITEC, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic.
Lukáš
L
Žídek
NCBR, Faculty of Science, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic; CEITEC, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic.
Vladimír
V
Sklenář
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, 3004, Australia.
Jack S
JS
Richards
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, 3004, Australia.
James G
JG
Beeson
Department of Biochemistry, La Trobe University, Victoria, 3086, Australia.
Robin F
RF
Anders
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052, Australia.
Raymond S
RS
Norton
D000953:Antigens, Protozoan / Q000737:chemistry* / Q000276:immunology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010963:Plasmodium falciparum / Q000276:immunology*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry* / Q000276:immunology*
D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C065974:merozoite surface protein 2, Plasmodium