Department of Biochemistry, University of Oxford, Oxford, United Kingdom; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, United Kingdom
Cristina F Constantin
Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Stephan Hirschi
Department of Biochemistry, University of Oxford, Oxford, United Kingdom; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, United Kingdom
Sebastian Henrich
Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Wolfgang Bildl
Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Bernd Fakler
Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBS, Freiburg, Germany
Department of Biochemistry, University of Oxford, Oxford, United Kingdom; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, United Kingdom
Department of Biochemistry, University of Oxford, Oxford, United Kingdom; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, United Kingdom
Basigin is an essential host receptor for invasion of Plasmodium falciparum into human erythrocytes, interacting with parasite surface protein PfRH5. PfRH5 is a leading blood-stage malaria vaccine candidate and a target of growth-inhibitory antibodies. Here, we show that erythrocyte basigin is exclusively found in one of two macromolecular complexes, bound either to plasma membrane Ca2+-ATPase 1/4 (PMCA1/4) or to monocarboxylate transporter 1 (MCT1). PfRH5 binds to each of these complexes with a higher affinity than to isolated basigin ectodomain, making it likely that these are the physiological targets of PfRH5. PMCA-mediated Ca2+ export is not affected by PfRH5, making it unlikely that this is the mechanism underlying changes in calcium flux at the interface between an erythrocyte and the invading parasite. However, our studies rationalise the function of the most effective growth-inhibitory antibodies targeting PfRH5. While these antibodies do not reduce the binding of PfRH5 to monomeric basigin, they do reduce its binding to basigin-PMCA and basigin-MCT complexes. This indicates that the most effective PfRH5-targeting antibodies inhibit growth by sterically blocking the essential interaction of PfRH5 with basigin in its physiological context.
