RT Journal Article SR Electronic T1 Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.09.23.509221 DO 10.1101/2022.09.23.509221 A1 Jamwal, Abhishek A1 Constantin, Cristina E. A1 Henrich, Sebastian A1 Bildl, Wolfgang A1 Fakler, Bernd A1 Draper, Simon J. A1 Schulte, Uwe A1 Higgins, Matthew K. YR 2022 UL http://biorxiv.org/content/early/2022/09/24/2022.09.23.509221.abstract AB 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. However, basigin is not alone on the erythrocyte surface. Instead, we show that it is exclusively found in one of two macromolecular complexes, bound predominantly to either plasma membrane Ca2+-ATPase 1/4, PMCA1/4, or monocarboxylate transporter 1, MCT1. PfRH5 binds to either 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, ruling this out as 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.Competing Interest StatementUS is an employee and shareholder of Logopharm GmbH and BF is shareholder of Logopharm GmbH. Logopharm GmbH produces ComplexioLyte 47 used in this study. The company provides ComplexioLyte reagents to academic institutions on a non-profit basis. MKH and SJD are named inventors on patents related to PfRH5-targeting antibodies.