Structure of the C-terminal Domains of Merozoite Surface Protein-1 from Plasmodium knowlesi Reveals a Novel Histidine Binding Site

Abstract

The protozoan parasite Plasmodium causes malaria, with hundreds of millions of cases recorded annually. Protection against malaria infection can be conferred by antibodies against merozoite surface protein (MSP)-1, making it an attractive vaccine candidate. Here we present the structure of the C-terminal domains of MSP-1 (known as MSP-1 19 ) from Plasmodium knowlesi. The structure reveals two tightly packed epidermal growth factor-like domains oriented head to tail. In domain 1, the molecule displays a histidine binding site formed primarily by a highly conserved tryptophan. The protein carries a pronounced overall negative charge primarily due to the large number of acidic groups in domain 2. To map protein binding surfaces on MSP-1 19 , we have analyzed the crystal contacts in five different crystal environments, revealing that domain 1 is highly preferred in protein-protein interactions. A comparison of MSP-1 19 structures from P. knowlesi, P. cynomolgi, and P. falciparum shows that, although the overall protein folds are similar, the molecules show significant differences in charge distribution. We propose the histidine binding site in domain 1 as a target for inhibitors of protein binding to MSP-1, which might prevent invasion of the merozoite into red blood cells.

Characterisation of PfRON6, a Plasmodium falciparum rhoptry neck protein with a novel cysteine-rich domain

“…S1). This is analogous to the dual EGF-like domains of MSP1 19 , where 10 out of 12 cysteines in P. falciparum are conserved in P. knowlesi and Plasmodium cynomolgi (Garman et al, 2003). …”

A Common Cross-species Function for the Double Epidermal Growth Factor-like Modules of the Highly Divergent Plasmodium Surface Proteins MSP-1 and MSP-8

“…The crystal and NMR structures of the P. falciparum MSP-1 EGF domains have been determined (26,36), as have the crystal structures for the P. cynomolgi and P. knowlesi versions of this molecule (37,38). All studies show that the MSP-1 EGF domains form a flat, almost disc-like structure with the two domains folded back on one another, not end-on-end as in some other multi-EGF domain proteins.…”

Structural Classification of Small, Disulfide-rich Protein Domains

“…Similarly, the C-terminal region of merozoite surface protein 1 contains a tandem repeat of EGF-like domains, but the first repeat in some Plasmodium species has only two of the three highly conserved disulfide bonds of the EGF-like domain family, while the second repeat has all three. 58 Numerous examples are seen in which a few proteins have additional disulfide bonds relative to the majority of family members. Some spider toxins (for example u-agatoxin IVa, pdbj1iva 59 or m-agatoxin I, pdbj1eit 60 ) have an additional disulfide bond on the key b-hairpin of their knottin-like fold.…”