title: 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 "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.
authors.affiliation: Immune Disease Institute, Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Doud
authors.forename: Adem C
authors.initials: AC
authors.lastname: Koksal
authors.forename: Li-Zhi
authors.initials: LZ
authors.lastname: Mi
authors.forename: Gaojie
authors.initials: G
authors.lastname: Song
authors.forename: Chafen
authors.initials: C
authors.lastname: Lu
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D003461:Crystallography; D057809:HEK293 Cells; D006801:Humans; D017780:Malaria Vaccines / Q000737:chemistry*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum; D017510:Protein Folding; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics; D053838:Scattering, Small Angle; D016415:Sequence Alignment; D034101:Sporozoites / Q000737:chemistry*
chemical_list: D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan