Structure of EPCR in a non-canonical conformation

Structural motion and conformational flexibility are often linked to biological functions of proteins. Whether the endothelial protein C receptor (EPCR), like other molecules, is vulnerable to folding transitions or might adopt alternative conformations remains unknown. The current understanding points to a rigid molecular structure suitable for binding of its ligands, like the anticoagulant protein C, or the CIDRα1 domains of Plasmodium falciparum . In this study, we have identified a novel conformation of EPCR, captured by X-ray diffraction analyses, whereby Tyr154 shows a dramatically altered structural arrangement, likely incompatible with protein C binding. Biolayer interferometry analysis confirms previous results supporting a critical role for this position in protein C binding. Importantly, the conformational change has no apparent effect in the bound lipid. We conclude these findings reveal a site of conformational vulnerability in EPCR and inform a highly malleable region that could modulate EPCR functions.