Unexpected fold in the circumsporozoite protein target of malaria vaccines.
Publication Type:Journal Article
Source:Proc Natl Acad Sci U S A, Volume 109, Issue 20, p.7817-22 (2012)
Keywords:Amino Acid Sequence, Chromatography, High Pressure Liquid, Crystallography, HEK293 Cells, Humans, Malaria Vaccines, Malaria, Falciparum, Mass Spectrometry, Models, Molecular, Molecular Sequence Data, Plasmodium falciparum, Protein Folding, Protozoan Proteins, Scattering, Small Angle, Sequence Alignment, Sporozoites
<p>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.</p>