Order, Disorder and Fibril Formation in the Malaria Vaccine Candidate MSP2

Abstract

Merozoite surface protein 2 (MSP2) is synthesized by asexual blood stages of the human malaria parasite Plasmodium falciparum as a GPI-anchored protein. It has been implicated in erythrocyte invasion and is being developed as a vaccine candidate. NMR, light scattering, CD and sedimentation velocity measurements all show that recombinant MSP2 is disordered in solution and adopts an extended conformation. NMR has also been used to examine peptides corresponding to sequences in the conserved N-terminal region of MSP2. A 25-residue peptide corresponding to the entire N-terminal region contains nascent helical and turn-like structures (1). An 8-residue peptide from the centre of the N-terminal domain also formed a turn-like structure (2). Both peptides formed fibrils that were similar to the amyloid-like fibrils formed by full-length MSP2. It appears that this N-terminal conserved region of MSP2 plays a key role in fibril formation. Mutational analyses are being pursued to understand the role of this region in structure and fibril formation (1). NMR resonance assignments have been obtained for full-length MSP2, allowing the residual secondary structure and backbone dynamics to be defined (3). There is some motional restriction in the conserved C-terminal region in the vicinity of an intramolecular disulfide bond. Two other regions show motional restrictions, both of which display helical structure propensities. One of these helical regions is within the conserved N-terminal domain, which adopts essentially the same conformation in full-length MSP2 as in corresponding peptide fragments. We see no evidence of long-range interactions in the full-Volume S2:070-071(2008)