Poster Presentation First Malaria World Congress 2018

Structure function analyses of the interactions between a Plasmodium vivax adhesin and the essential housekeeping protein Transferrin Receptor (#346)

Sebastien Menant 1 , Li Jin Chan 1 2 , Jakub Gruszczyk 1 , Wai-Hong Tham 1 2
  1. Walter+Eliza Hall Institute, Parkville, Victoria, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia

Malaria parasites are obligate intracellular parasites. Invasion into human red blood cells is critical to the survival of malaria parasites in the human host. Understanding how malaria parasites bind human red blood cells is essential for the development of strategies to stop blood stage infection. Parasite entry into red blood cells is governed by interactions between parasite adhesins and red blood cell receptors. Amongst the six human malaria parasite species, Plasmodium vivax invades exclusively young red blood cells called reticulocytes, though the reticulocyte-specific receptor has remained elusive. Our lab has identified that P. vivax uses transferrin receptor 1 (TfR1), an essential house-keeping protein, to mediate reticulocyte-recognition. We show that P. vivax Reticulocyte-binding protein 2b (PvRBP2b) forms a stable complex with TfR1 and its human ligand transferrin. Using structural biology techniques, we have identified amino acid residues at the TfR1-PvRBP2b binding interface. Sequence alignment of several mammalian orthologs of TfR1 reveal that several human TfR1 residues are not conserved across species despite a high degree of sequence identity. We will determine if these differences govern P. vivax selective entry into human reticulocytes. In addition, to understand the structure-function relationships between PvRBP2b-TfR1, we have expressed and purified mutant variants of this ligand-receptor pair. Using a flow cytometry-based red blood cell binding assay and size exclusion chromatography to monitor complex formation, we show that several key sites on both PvRBP2b and TfR1 are critical for the function of these proteins in red blood cell binding and complex formation. Characterization of the critical amino acids required for the formation of the TfR1-PvRBP2b complex provides a framework for epitope design for immunogens that block P. vivax blood stage infection.

  1. Gruszczyk J, Kanjee U, Chan LJ, Menant S, Malleret B, Lim NTY, Schmidt CQ, Mok YF, Lin KM, Pearson RD, Rangel G, Smith BJ, Call MJ, Weekes MP, Griffin MDW, Murphy JM, Abraham J, Sriprawat K, Menezes MJ, Ferreira MU, Russell B, Renia L, Duraisingh MT, Tham WH. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science. 2018 Jan 5;359(6371):48-55.