Unexpected fold in the circumsporozoite protein target of malaria vaccines.

ABSTRACT: 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 "?TSR" domain. The ?TSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but ?TSR does not. Interestingly, polymorphic T-cell epitopes map to specialized ?TSR 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.

SUBMITTER: Doud MB 

PROVIDER: S-EPMC3356675 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature