Intrinsically disordered proteins are highly abundant in the malaria parasite Plasmodium and related pathogens.[1] Merozoite surface protein 2 (MSP2) is an intrinsically disordered membrane antigen of P. falciparum [2] that is highly abundant on the surface of merozoites and elicits a protective response in humans. Furthermore, our recent analysis of antibody recognition of disordered antigens shows that disordered antigens are bona fide vaccine candidates.[3]
Crystallographic and NMR studies show[4] that recognition of a conserved N-terminal epitope from MSP2 by the mAb 6D8 is incompatible with the membrane-bound conformation of this epitope,[5] suggesting a mechanism by which parasite MSP2 escapes 6D8 recognition. Intriguingly, NMR also identifies transient, strain-specific interactions between the 6D8 mAb and regions of MSP2 beyond the conserved epitope. Even though these interactions are transient they nonetheless modulate the affinity of these epitopes, either as peptides or full-length antigens, for the antibody.
The conserved C-terminal region of MSP2 is recognised by mAbs 4D11 and 9H4. 4D11 binds to merozoites much more strongly than 9H4. A crystal structure of 4D11 Fv bound to the epitope NKENCGAA reveals the possible conformation of the C-terminal region of MSP2 on the parasite.[6] The results of these studies underpin ongoing efforts to optimize recombinant MSP2 constructs for development as malaria vaccine candidates.
[1] Z. P. Feng, et al., Mol. Biochem. Parasitol. 2006, 150, 256.
[2] X. Zhang, et al., J. Mol. Biol. 2008, 379, 105.
[3] C. A. MacRaild, et al., Structure 2016, 24, 148.
[4] R. A. V. Morales, et al., Sci Rep 2015, 5, 10103.
[5] C. A. MacRaild, et al., Biochim. Biophys. Acta 2012, 1818, 2572.
[6] J. Seow, et al., J. Mol. Biol. 2017, 429, 836.