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

Campeotto, I ORCID: https://orcid.org/0000-0002-0814-619X, Galaway, F, Mehmood, S, Barfod, LK, Quinkert, D, Kotraiah, V, Phares, TW, Wright, KE, Snijders, AP, Draper, SJ, Higgins, MK and Wright, GJ, 2020. The structure of the cysteine-rich domain of Plasmodium falciparum P113 identifies the location of the RH5 binding site. mBio, 11 (5): e01566-20. ISSN 2150-7511

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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.

Item Type:	Journal article
Publication Title:	mBio
Creators:	Campeotto, I., Galaway, F., Mehmood, S., Barfod, L.K., Quinkert, D., Kotraiah, V., Phares, T.W., Wright, K.E., Snijders, A.P., Draper, S.J., Higgins, M.K. and Wright, G.J.
Publisher:	American Society for Microbiology
Date:	8 September 2020
Volume:	11
Number:	5
ISSN:	2150-7511
Identifiers:	Number Type 10.1128/mbio.01566-20 DOI 1375378 Other
Rights:	Copyright © 2020 Campeotto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Divisions:	Schools > School of Science and Technology
Record created by:	Jill Tomkinson
Date Added:	27 Oct 2020 11:02
Last Modified:	31 May 2021 15:13
URI:	https://irep.ntu.ac.uk/id/eprint/41413

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