National Center for
3VDL: Crystal Structure Of Circumsporozoite Protein Atsr Domain, P43212 Form
Proc. Natl. Acad. Sci. U. S. A. (2012) 109 p.7817-7822
Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an "alphaTSR" domain. The alphaTSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but alphaTSR does not. Interestingly, polymorphic T-cell epitopes map to specialized alphaTSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket.