Reversible conformational change in the plasmodium falciparum circumsporozoite protein masks Its adhesion domains

Raul Herrera, Charles Anderson, Krishan Kumar, Alvaro Molina-Cruz, Vu Nguyen, Martin Burkhardt, Karine Reiter, Richard Shimp, Randall F. Howard, Prakash Srinivasan, Michael J. Nold, Daniel Ragheb, Lirong Shi, Mark DeCotiis, Joan Aebig, Lynn Lambert, Kelly M. Rausch, Olga Muratova, Albert Jin, Steven G. ReedPhotini Sinnis, Carolina Barillas-Mury, Patrick E. Duffy, Nicholas J. MacDonald, David L. Naruma

Research output: Contribution to journalArticle

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 eroepidemiological 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.

Original languageEnglish (US)
Pages (from-to)3771-3780
Number of pages10
JournalInfection and immunity
Volume83
Issue number10
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Reversible conformational change in the plasmodium falciparum circumsporozoite protein masks Its adhesion domains'. Together they form a unique fingerprint.

  • Cite this

    Herrera, R., Anderson, C., Kumar, K., Molina-Cruz, A., Nguyen, V., Burkhardt, M., Reiter, K., Shimp, R., Howard, R. F., Srinivasan, P., Nold, M. J., Ragheb, D., Shi, L., DeCotiis, M., Aebig, J., Lambert, L., Rausch, K. M., Muratova, O., Jin, A., ... Naruma, D. L. (2015). Reversible conformational change in the plasmodium falciparum circumsporozoite protein masks Its adhesion domains. Infection and immunity, 83(10), 3771-3780. https://doi.org/10.1128/IAI.02676-14