Oral Presentation 2014 International Biophysics Congress

Understanding the immune interactions of an unstructured protein antigen: The malaria surface protein MSP2 (#173)

Christopher A. MacRaild 1 , Rodrigo Morales 1 , Jeffrey Seow 1 , Sheena McGowan 2 , Robin F. Anders 3 , Raymond S. Norton 1
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  2. Department of Biochemistry, Monash University, Clayton, VIC, Australia
  3. Department of Biochemistry, La Trobe University, Bundoora, VIC, Australia

MSP2 is an abundant GPI-anchored protein found on the surface of Plasmodium falciparum merozoites and is considered a potential component of a malaria vaccine. MSP2 comprises conserved N- and C- terminal regions flanking a central polymorphic region containing repetitive and non-repetitive sequences. Like many malaria antigens, MSP2 is intrinsically unstructured, with few regions of limited conformational restriction in solution.1 The structural basis and functional significance of immune interactions with unstructured proteins are poorly understood.
Analyses using a panel of monoclonal antibodies indicate that parasite MSP2 is antigenically distinct from recombinant MSP2, implying that the conformation of the protein on the parasite surface differs from that in solution. This results in preferential exposure of the highly variable central region of MSP2 on the merozoite surface.2 Moreover, antibodies directed against conserved epitopes in MSP2 show unexpected strain-specificity, demonstrating that regions of sequence identity in orthologous disordered proteins are not necessarily antigenically identical. We have used NMR spectroscopy and X-ray crystallography to characterise the structure of MSP2 free in solution, bound to lipid membranes, and bound to monoclonal antibodies. In this way, we are revealing structural details of the interactions that underpin the antigenic properties of MSP2. These insights will be exploited in the optimization of MSP2 as a malaria vaccine component.

  1. 1. X. Zhang et al. (2008). J. Mol. Biol. 379: 105-121
  2. 2. C.G. Adda et al. (2012) Infect. Immun. 80: 4177-4185