Malaria adhesins: structure and function

Abstract

The malaria parasite Plasmodium utilizes specialized proteins for adherence to cellular receptors in its mosquito vector and human host. Adherence is critical for parasite development, host cell traversal and invasion, and protection from vector and host immune mechanisms. These vital roles have identified several adhesins as vaccine candidates. A deficiency in current adhesin-based vaccines is induction of antibodies targeting non-conserved, non-functional and decoy epitopes due to the use of full length proteins or binding domains. To alleviate the elicitation of non-inhibitory antibodies, conserved functional regions of proteins must be identified and exploited. Structural biology provides the tools necessary to achieve this goal, and has succeeded in defining biologically functional receptor binding and oligomerization interfaces for a number of promising malaria vaccine candidates. We describe here the current knowledge of Plasmodium adhesin structure and function, and how it has illuminated elements of parasite biology and defined interactions at the host/vector and parasite interface.

Fig. 1

Domain architectures of adhesive proteins functioning at different parasite life stages. For families with a varied number and/or organization of adhesive domains, the most well characterized member of the family is shown. The domains are color coded and identified in the two boxes within the figure.

Fig. 2

Crystal structures define adhesive folds used by the malaria parasite. A. The structure of Pf12, representing the s48/45 domain. Members of the 6-cys family exhibit a range in their number of tandem s48/45 domains and function at multiple life cycle stages. B. p25 utilizes four tandem EGF-like domains for adhesion (left). The four EGF domains are shown on the left in different colors for clarity. Extensive contact between p25 monomers was observed in the crystal packing arrangement, and these contacts are proposed to play a role in parasite surface coat formation (crystal packing arrangement shown on the right). The middle p25 monomer, shown in red, is equivalent to the p25 monomer shown on the left, while adjacent, contacting monomers are shown in black and grey. C. MSP1-19 contains two tandem EGF-like domains, shown in red, involved in RBC binding. MSP1-19 displays extensive contact between the two EGFs, resulting in a rigid structure that contrasts other tandem EGF domain structures D. CSP Region III-TSR forms a rigid domain designated the α-TSR. Region III (grey) and the TSR (green) make extensive contacts. E. PfEBA-175 engages its receptor Glycophorin A as a dimer. DBL domains are shown in blue for one PfEBA-175 monomer, and in grey for the second monomer that forms the dimeric complex during receptor engagement. The parasite membrane is shown in grey; the host RBC membrane is shown in red. F. Binding of receptor DARC to PvDBP drives dimerization of this complex. The sole DBL domain of RII is shown in blue, while the contacting DBL domain from a second PvDBP is shown in grey. The parasite membrane is shown in grey; the host RBC membrane is shown in red. G. PfEBA-140 appears to bind as a monomer to its receptor Glycophorin C. The tandem DBL domains of RII are shown in blue. The parasite membrane is shown in grey; the host RBC membrane is shown in red. H. AMA-1 (orange/brown) binds the parasite expressed RON2 (purple), a member of the RON complex, which is released by the parasite into the RBC during invasion. AMA-1 is linked to cytoplasmic aldolase (light green) within the parasite. The parasite membrane is shown in grey; the host RBC membrane is shown in red. I. The link to the parasite’s internal actin motor through cytoplasmic aldolase (light green) is formed by TRAP, with functions on the sporozoite. The VWA domain is shown in cyan and the TSR domain in green. A unique member of the TRAP family functions at each parasite life stage and utilizes a combination of the VWA and TSR domains. The parasite membrane is shown in grey; the host cell membrane (mosquito salivary gland and human hepatocyte), is shown in yellow. J. During growth in the RBC, the parasite exports PfEMP1 to the RBC surface, where these proteins utilize a combination of the DBL (blue) and helical CIDR (brown) domains to adhere to a wide range of human surface receptors. The N-terminal element (purple) makes extensive contact with the DBL domain.