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Plasmodium falciparum  is an apicomplexan parasite and the etiological agent of severe human malaria. The complex  P .  falciparum  life cycle is supported by a diverse repertoire of surface proteins including the family of 6-Cys s48/45 antigens. Of these,  Pf 41 is localized to the surface of the blood-stage merozoite through its interaction with the glycophosphatidylinositol-anchored  Pf 12. Our recent structural characterization of  Pf 12 revealed two juxtaposed 6-Cys domains (D1 and D2).  Pf 41, however, contains an additional segment of 120 residues predicted to form a large spacer separating its two 6-Cys domains. To gain insight into the assembly mechanism and overall architecture of the  Pf 12- Pf 41 complex, we first determined the 2.45 Å resolution crystal structure of  Pf 41 using zinc single-wavelength anomalous dispersion. Structural analysis revealed an unexpected domain organization where the  Pf 41 6-Cys domains are, in fact, intimately associated and the additional residues instead map predominately to an inserted domain-like region (ID) located between two β-strands in D1. Notably, the ID is largely proteolyzed in the final structure suggesting inherent flexibility. To assess the contribution of the ID to complex formation, we engineered a form of  Pf 41 where the ID was replaced by a short glycine-serine linker and showed by isothermal titration calorimetry that binding to  Pf 12 was abrogated. Finally, protease protection assays showed that the proteolytic susceptibility of the ID was significantly reduced in the complex, consistent with the  Pf 41 ID directly engaging  Pf 12. Collectively, these data establish the architectural organization of  Pf 41 and define an essential role for the  Pf 41 ID in promoting assembly of the  Pf 12- Pf 41 heterodimeric complex.

The Structure of Plasmodium falciparum Blood-Stage 6-Cys Protein Pf41 Reveals an Unexpected Intra-Domain Insertion Required for Pf12 Coordination