Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate

Rodrigo De Almeida Vilela Morales, Christopher Andrew MacRaild, Jeffrey Tien-Jie Seow, Bankala Krishnarjuna, Nyssa Drinkwater, Romain Rouet, Robin Fredric Anders, Daniel Christ, Sheena McGowan, Raymond Stanley Norton

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Merozoite surface protein 2 (MSP2) is an intrinsically disordered, membrane-anchored antigen of the malaria parasite Plasmodium falciparum. MSP2 can elicit a protective, albeit strain-specific, antibody response in humans. Antibodies are generated to the conserved N- and C-terminal regions but many of these react poorly with the native antigen on the parasite surface. Here we demonstrate that recognition of a conserved N-terminal epitope by mAb 6D8 is incompatible with the membrane-bound conformation of that region, suggesting a mechanism by which native MSP2 escapes antibody recognition. Furthermore, crystal structures and NMR spectroscopy identify transient, strain-specific interactions between the 6D8 antibody and regions of MSP2 beyond the conserved epitope. These interactions account for the differential affinity of 6D8 for the two allelic families of MSP2, even though 6D8 binds to a fully conserved epitope. These results highlight unappreciated mechanisms that may modulate the specificity and efficacy of immune responses towards disordered antigens.
Original languageEnglish
Article number10103
Number of pages10
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 2015

Cite this

De Almeida Vilela Morales, Rodrigo ; MacRaild, Christopher Andrew ; Seow, Jeffrey Tien-Jie ; Krishnarjuna, Bankala ; Drinkwater, Nyssa ; Rouet, Romain ; Anders, Robin Fredric ; Christ, Daniel ; McGowan, Sheena ; Norton, Raymond Stanley. / Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate. In: Scientific Reports. 2015 ; Vol. 5.
@article{6f714d3ead6545a8b6aa7cdac14d2c62,
title = "Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate",
abstract = "Merozoite surface protein 2 (MSP2) is an intrinsically disordered, membrane-anchored antigen of the malaria parasite Plasmodium falciparum. MSP2 can elicit a protective, albeit strain-specific, antibody response in humans. Antibodies are generated to the conserved N- and C-terminal regions but many of these react poorly with the native antigen on the parasite surface. Here we demonstrate that recognition of a conserved N-terminal epitope by mAb 6D8 is incompatible with the membrane-bound conformation of that region, suggesting a mechanism by which native MSP2 escapes antibody recognition. Furthermore, crystal structures and NMR spectroscopy identify transient, strain-specific interactions between the 6D8 antibody and regions of MSP2 beyond the conserved epitope. These interactions account for the differential affinity of 6D8 for the two allelic families of MSP2, even though 6D8 binds to a fully conserved epitope. These results highlight unappreciated mechanisms that may modulate the specificity and efficacy of immune responses towards disordered antigens.",
author = "{De Almeida Vilela Morales}, Rodrigo and MacRaild, {Christopher Andrew} and Seow, {Jeffrey Tien-Jie} and Bankala Krishnarjuna and Nyssa Drinkwater and Romain Rouet and Anders, {Robin Fredric} and Daniel Christ and Sheena McGowan and Norton, {Raymond Stanley}",
year = "2015",
doi = "10.1038/srep10103",
language = "English",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate. / De Almeida Vilela Morales, Rodrigo; MacRaild, Christopher Andrew; Seow, Jeffrey Tien-Jie; Krishnarjuna, Bankala; Drinkwater, Nyssa; Rouet, Romain; Anders, Robin Fredric; Christ, Daniel; McGowan, Sheena; Norton, Raymond Stanley.

In: Scientific Reports, Vol. 5, 10103 , 2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate

AU - De Almeida Vilela Morales, Rodrigo

AU - MacRaild, Christopher Andrew

AU - Seow, Jeffrey Tien-Jie

AU - Krishnarjuna, Bankala

AU - Drinkwater, Nyssa

AU - Rouet, Romain

AU - Anders, Robin Fredric

AU - Christ, Daniel

AU - McGowan, Sheena

AU - Norton, Raymond Stanley

PY - 2015

Y1 - 2015

N2 - Merozoite surface protein 2 (MSP2) is an intrinsically disordered, membrane-anchored antigen of the malaria parasite Plasmodium falciparum. MSP2 can elicit a protective, albeit strain-specific, antibody response in humans. Antibodies are generated to the conserved N- and C-terminal regions but many of these react poorly with the native antigen on the parasite surface. Here we demonstrate that recognition of a conserved N-terminal epitope by mAb 6D8 is incompatible with the membrane-bound conformation of that region, suggesting a mechanism by which native MSP2 escapes antibody recognition. Furthermore, crystal structures and NMR spectroscopy identify transient, strain-specific interactions between the 6D8 antibody and regions of MSP2 beyond the conserved epitope. These interactions account for the differential affinity of 6D8 for the two allelic families of MSP2, even though 6D8 binds to a fully conserved epitope. These results highlight unappreciated mechanisms that may modulate the specificity and efficacy of immune responses towards disordered antigens.

AB - Merozoite surface protein 2 (MSP2) is an intrinsically disordered, membrane-anchored antigen of the malaria parasite Plasmodium falciparum. MSP2 can elicit a protective, albeit strain-specific, antibody response in humans. Antibodies are generated to the conserved N- and C-terminal regions but many of these react poorly with the native antigen on the parasite surface. Here we demonstrate that recognition of a conserved N-terminal epitope by mAb 6D8 is incompatible with the membrane-bound conformation of that region, suggesting a mechanism by which native MSP2 escapes antibody recognition. Furthermore, crystal structures and NMR spectroscopy identify transient, strain-specific interactions between the 6D8 antibody and regions of MSP2 beyond the conserved epitope. These interactions account for the differential affinity of 6D8 for the two allelic families of MSP2, even though 6D8 binds to a fully conserved epitope. These results highlight unappreciated mechanisms that may modulate the specificity and efficacy of immune responses towards disordered antigens.

UR - http://www.nature.com/articles/srep10103.pdf

U2 - 10.1038/srep10103

DO - 10.1038/srep10103

M3 - Article

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 10103

ER -