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Proc Natl Acad Sci U S A. 2012 May 15;109(20):7817-22. doi: 10.1073/pnas.1205737109. Epub 2012 Apr 30.

Unexpected fold in the circumsporozoite protein target of malaria vaccines.

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1
Immune Disease Institute, Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

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

PMID:
22547819
PMCID:
PMC3356675
DOI:
10.1073/pnas.1205737109
[Indexed for MEDLINE]
Free PMC Article
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