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The structure of the cysteine-rich domain of Plasmodium falciparum P113 identifies the location of the RH5 binding site

DOI: 10.1128/mBio.01566-20 DOI Help

Authors: Ivan Campeotto (University of Oxford; Nottingham Trent University) , Francis Galaway (Wellcome Trust Sanger Institute) , Shahid Mehmood (The Francis Crick Institute) , Lea K. Barfod (The Jenner Institute, University of Oxford) , Doris Quinkert (The Jenner Institute, University of Oxford) , Vinayaka Kotraiah (Leidos Inc) , Timothy W. Phares (Leidos Inc) , Katherine E. Wright (University of Oxford) , Ambrosius P. Snijders (The Francis Crick Institute) , Simon J. Draper (The Jenner Institute, University of Oxford) , Matthew K. Higgins (University of Oxford) , Gavin J. Wright (Wellcome Trust Sanger Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mbio , VOL 11

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 23459

Open Access Open Access

Abstract: Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins, CyRPA and RIPR, and is tethered to the surface of the parasite through membrane-anchored P113. Antibodies against RH5, CyRPA, and RIPR can inhibit parasite invasion, suggesting that vaccines containing these three components have the potential to prevent blood-stage malaria. To further explore the role of the P113-RH5 interaction, we selected monoclonal antibodies against P113 that were either inhibitory or noninhibitory for RH5 binding. Using a Fab fragment as a crystallization chaperone, we determined the crystal structure of the RH5 binding region of P113 and showed that it is composed of two domains with structural similarities to rhamnose-binding lectins. We identified the RH5 binding site on P113 by using a combination of hydrogen-deuterium exchange mass spectrometry and site-directed mutagenesis. We found that a monoclonal antibody to P113 that bound to this interface and inhibited the RH5-P113 interaction did not inhibit parasite blood-stage growth. These findings provide further structural information on the protein interactions of RH5 and will be helpful in guiding the development of blood-stage malaria vaccines that target RH5.

Journal Keywords: Plasmodium falciparum; crystal structure; malaria; monoclonal antibodies; protein-protein interaction; svaccines

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography