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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 Ca 2+ -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 Ca 2+ 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., Competing Interests: AJ, CC, SH, WB No competing interests declared, SH is affiliated with Roche Pharma AG. The author has no financial interests to declare, BF is a 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, SD is a named inventor on patents related to PfRH5-targeting antibodies.(PCT/GB2105/052205, PCT/GB2017/052608 and PCT/GB2019/052885), US 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, MH US 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.named inventor on patents related to PfRH5-targeting antibodies (PCT/GB2105/052205, PCT/GB2017/052608 and PCT/GB2019/052885), (© 2023, Jamwal et al.)