1. Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains.
- Author
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Herrera R, Anderson C, Kumar K, Molina-Cruz A, Nguyen V, Burkhardt M, Reiter K, Shimp R Jr, Howard RF, Srinivasan P, Nold MJ, Ragheb D, Shi L, DeCotiis M, Aebig J, Lambert L, Rausch KM, Muratova O, Jin A, Reed SG, Sinnis P, Barillas-Mury C, Duffy PE, MacDonald NJ, and Narum DL
- Subjects
- Animals, Anopheles parasitology, Antibodies, Protozoan immunology, Epitopes chemistry, Epitopes genetics, Epitopes immunology, Hepatocytes immunology, Hepatocytes parasitology, Humans, Malaria, Falciparum immunology, Plasmodium falciparum chemistry, Plasmodium falciparum genetics, Plasmodium falciparum growth & development, Protein Conformation, Protein Structure, Tertiary, Protozoan Proteins genetics, Sporozoites chemistry, Sporozoites growth & development, Malaria, Falciparum parasitology, Plasmodium falciparum immunology, Protozoan Proteins chemistry, Protozoan Proteins immunology, Sporozoites immunology
- Abstract
The extended rod-like Plasmodium falciparum circumsporozoite protein (CSP) is comprised of three primary domains: a charged N terminus that binds heparan sulfate proteoglycans, a central NANP repeat domain, and a C terminus containing a thrombospondin-like type I repeat (TSR) domain. Only the last two domains are incorporated in RTS,S, the leading malaria vaccine in phase 3 trials that, to date, protects about 50% of vaccinated children against clinical disease. A seroepidemiological study indicated that the N-terminal domain might improve the efficacy of a new CSP vaccine. Using a panel of CSP-specific monoclonal antibodies, well-characterized recombinant CSPs, label-free quantitative proteomics, and in vitro inhibition of sporozoite invasion, we show that native CSP is N-terminally processed in the mosquito host and undergoes a reversible conformational change to mask some epitopes in the N- and C-terminal domains until the sporozoite interacts with the liver hepatocyte. Our findings show the importance of understanding processing and the biophysical change in conformation, possibly due to a mechanical or molecular signal, and may aid in the development of a new CSP vaccine., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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