Fig. 1.

Sequence alignments and fold schematics. (A) Gene architecture of P. falciparum circumsporozoite protein. The portion of CS fused to hepatitis B surface antigen in the RTS,S vaccine is indicated by “vaccine.” (B) C-terminal portion of CS from different species. Conserved residues are colored according to chemical type. Disulfide-linked cysteines are colored according to connectivity. Dots below green (hydrophobic) columns mark residues in the hydrophobic core (blue) or exposed hydrophobic pocket (orange). Secondary structure is designated below the alignment by thick lines (helices and β-strands) colored by TSR strand direction (cyan and pink are antiparallel strand directions). Shannon sequence entropy was calculated from 42 distinct P. falciparum isolates from Freetown, Sierra Leone (27) using the Protein Variability Server (46). (C) Alignment with TSR domains from F-spondin (FSP) (9), thrombospondin-1 (TSP1) (7), and ADAMTS13 (10). Unique portions of PfCS αTSR are overlined in orange. Only sequences overlined in identical colors are structurally equivalent. Segments forming sheets or helices are shown with thickened lines. Disulfide connectivity is color coded. P. falciparum CS (3D7 strain) mature numbering is shown above the sequences. TSR consensus residues are shown below the alignment. (D) Diversity of TSR domain architectures, modified from ref. 7.