Characterization of inhibitors and monoclonal antibodies that modulate the interaction between Plasmodium falciparum adhesin PfRh4 with its erythrocyte receptor complement receptor 1
- Author(s)
- Lim, NT; Harder, MJ; Kennedy, AT; Lin, CS; Weir, C; Cowman, AF; Call, MJ; Schmidt, CQ; Tham, WH;
- Details
- Publication Year 2015-08-31,Volume 290,Issue #42,Page 25307-25321
- Journal Title
- Journal of Biological Chemistry
- Publication Type
- Journal Article
- Abstract
- Plasmodium falciparum parasites must invade red blood cells in order to survive within humans. Entry into red blood cells is governed by interactions between parasite adhesins and red blood cell receptors. Previously we identified that P. falciparum Reticulocyte Binding protein-like homologue 4 (PfRh4) binds to Complement Receptor 1 (CR1) to mediate entry of malaria parasites into human red blood cells. In this report, we characterize a collection of anti-PfRh4 monoclonal antibodies and CR1 protein fragments that modulate the interaction between PfRh4 and CR1. We identify an anti-PfRh4 monoclonal that blocks PfRh4-CR1 interaction in vitro, inhibits PfRh4 binding to red blood cells and as a result abolishes the PfRh4-CR1 invasion pathway in P. falciparum. Epitope mapping of anti-PfRh4 monoclonal antibodies identified distinct functional regions within PfRh4 involved in modulating its interaction with CR1. Furthermore, we designed a set of protein fragments based on extensive mutagenesis analyses of the PfRh4 binding site on CR1 and determined their interaction affinities using surface plasmon resonance. These CR1 protein fragments bind tightly to PfRh4 and also function as soluble inhibitors to block PfRh4 binding to red blood cells and to inhibit the PfRh4-CR1 invasion pathway. Our findings can aid future efforts in designing specific single epitope antibodies to block P. falciparum invasion via Complement Receptor 1.
- Publisher
- ASBM
- Research Division(s)
- Infection And Immunity; Structural Biology
- PubMed ID
- 26324715
- Publisher's Version
- https://doi.org/10.1074/jbc.M115.657171
- NHMRC Grants
- NHMRC/1026581,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-09-24 02:12:26
Last Modified: 2016-02-10 09:50:29