The crystal structure of the erythrocyte-binding domain of a key malaria-vaccine candidate protein, both with and without its sugar ligand, has been published in Cell.

The complex malaria lifecycle includes the invasion of erythrocytes by a blood-stage parasite form, the merozoite, which results in the parasite stage that causes the onset of all the clinical symptoms of malaria. As the bloodborne merozoites are shortlived, disruption of the invasion step could control this debilitating and often fatal disease.

During invasion, the erythrocyte invasion antigen EBA-175 binds to the main erythrocyte glycoprotein, glycophorin A. The conserved RII domain of this antigen contains two Duffy-binding-like domains (DBL) that contain conserved motifs found in members of the erythrocyte-binding-like protein (EBL) superfamily. Different members of this family bind to different erythrocyte surface proteins, so that erythrocyte invasion might proceed through several different mechanisms. The EBL family is widespread among Plasmodium species but is restricted to this genus, so these proteins are excellent drug and vaccine targets.

Tolia et al. solved the crystal structure of EBA-175 RII to 2.3-Å resolution, both with and without a glycan ligand. Two monomers of RII crystallized as a dimer and were aligned antiparallel, forming two internal channels. According to the authors, this arrangement mimics a handshake. When the glycan α-2,3-sialyllactose was cocrystallized with the RII dimer, six sugar-binding sites were identified. All six sugars were bound in the dimer interface and contacted both monomers.

The RII dimer seems to grip the sugar molecules, as four of the six sugar-binding sites are in the two channels formed by RII dimerization. The authors hypothesize that the RII protein only dimerizes when it contacts the erythrocyte surface glycoprotein glycophorin A, consistent with biochemical evidence that the predominant form of RII in solution is a monomer.

Dimerization of the extracellular RII domain of EBA-175 causes a conformational change that results in signalling by the cytoplasmic portion of the protein that in turn mediates invasion. So, the structure of the dimer could be used to inform invasion pathways that are mediated by other EBL proteins.

This novel structure will be useful to anyone wishing to model interactions involving DBL-containing proteins, and should be useful to those searching for drugs that can treat the symptoms of malaria.