Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein

Tossapol Pholcharee, David Oyen, Jonathan L. Torres, Yevel Flores-Garcia, Gregory M. Martin, Gonzalo E. González-Páez, Daniel Emerling, Wayne Volkmuth, Emily Locke, C. Richter King, Fidel Zavala, Andrew B. Ward, Ian A. Wilson

Research output: Contribution to journalArticle

Abstract

Malaria vaccine candidate RTS,S/AS01 is based on the central and C-terminal regions of the circumsporozoite protein (CSP) of P. falciparum. mAb397 was isolated from a volunteer in an RTS,S/AS01 clinical trial, and it protects mice from infection by malaria sporozoites. However, mAb397 originates from the less commonly used VH3-15 germline gene compared to the VH3-30/33 antibodies generally elicited by RTS,S to the central NANP repeat region of CSP. The crystal structure of mAb397 with an NPNA4 peptide shows that the central NPNA forms a type I β-turn and is the main recognition motif. In most anti-NANP antibodies studied to date, a germline-encoded Trp is used to engage the Pro in NPNA β-turns, but here the Trp interacts with the first Asn. This “conserved” Trp, however, can arise from different germline genes and be located in the heavy or the light chain. Variation in the terminal ψ angles of the NPNA β-turns results in different dispositions of the subsequent NPNA and, hence, different stoichiometries and modes of antibody binding to rsCSP. Diverse protective antibodies against NANP repeats are therefore not limited to a single germline gene response or mode of binding.

Original languageEnglish (US)
JournalJournal of molecular biology
DOIs
StateAccepted/In press - Jan 1 2020

Fingerprint

Plasmodium falciparum
Antibody Formation
Antibodies
Genes
Malaria Vaccines
Sporozoites
Malaria
Volunteers
Anti-Idiotypic Antibodies
Proteins
Clinical Trials
Light
Peptides
Infection
Protozoan circumsporozoite protein

Keywords

  • malaria
  • NANP repeats
  • sporozoite
  • Trp-Asn interaction
  • type I β-turn

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Pholcharee, T., Oyen, D., Torres, J. L., Flores-Garcia, Y., Martin, G. M., González-Páez, G. E., ... Wilson, I. A. (Accepted/In press). Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein. Journal of molecular biology. https://doi.org/10.1016/j.jmb.2019.12.029

Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein. / Pholcharee, Tossapol; Oyen, David; Torres, Jonathan L.; Flores-Garcia, Yevel; Martin, Gregory M.; González-Páez, Gonzalo E.; Emerling, Daniel; Volkmuth, Wayne; Locke, Emily; King, C. Richter; Zavala, Fidel; Ward, Andrew B.; Wilson, Ian A.

In: Journal of molecular biology, 01.01.2020.

Research output: Contribution to journalArticle

Pholcharee, T, Oyen, D, Torres, JL, Flores-Garcia, Y, Martin, GM, González-Páez, GE, Emerling, D, Volkmuth, W, Locke, E, King, CR, Zavala, F, Ward, AB & Wilson, IA 2020, 'Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein', Journal of molecular biology. https://doi.org/10.1016/j.jmb.2019.12.029
Pholcharee, Tossapol ; Oyen, David ; Torres, Jonathan L. ; Flores-Garcia, Yevel ; Martin, Gregory M. ; González-Páez, Gonzalo E. ; Emerling, Daniel ; Volkmuth, Wayne ; Locke, Emily ; King, C. Richter ; Zavala, Fidel ; Ward, Andrew B. ; Wilson, Ian A. / Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein. In: Journal of molecular biology. 2020.
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AU - Martin, Gregory M.

AU - González-Páez, Gonzalo E.

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