EPCR-binding PfEMP subtypes use CIDRα1 domains with overlapping EPCR-binding sites to protein C/APC to restrict protein C pathway function. (A) PfEMP subtypes expressing domain cassettes DC8 and DC13 that include CIDRα1.1 and CIDRα1.4-1.8 domains bind EPCR with high affinity. EPCR-binding CIDRα1 domains appear to use a similar binding mechanism and binding site to that of protein C/APC (blue). As CIDRα1 domains are significantly larger than the EPCR-binding region of protein C/APC, EPCR-binding CIDRα1 domains make additional extended contacts with EPCR via loops containing amino acid residues 22 to 25 and 44 to 47 (pink). However, despite the significant overlap, amino acid residues that include Glu-86 (yellow) have been identified that are crucial for protein C/APC binding, but not PfEMP1. Accordingly, recombinant variants of sEPCR in which Glu-86 has been substituted have been proposed as a potential therapeutic strategy to competitively impede EPCR-binding PfEMP subtypes enabling IE cytoadherence to the vasculature, preventing blockade of EPCR-dependent protein C activation (B) and PAR1 cytoprotective signaling by APC (C).