Endothelial protein C receptor (EPCR) also known as activated protein C receptor (APC receptor) is a protein that in humans is encoded by the PROCR gene. PROCR has also recently been designated CD201 (cluster of differentiation 201). EPCR is a transmembrane glycoprotein receptor that plays a crucial role in regulation of blood coagulation, inflammation, and vascular integrity. Its ability to enhance the anticoagulant activity of protein C, modulate inflammatory responses, and maintain endothelial barrier function highlights its importance in homeostasis maintanance.

Structure

EPCR protein is an N-glycosylated type I membrane protein that enhances the activation of protein C. It belongs to the MHC class I/CD1 family of proteins, The structure of CD201 consists of an extracellular domain, a transmembrane domain, and a cytoplasmic tail. The extracellular domain of CD201 contains a high-affinity binding site for activated protein C (APC), a serine protease with anticoagulant properties. The binding site for APC resembles a deep groove with a lipid inside. The bound lipid in EPCR is usually phosphatidylcholine or phosphatidylethanolamine, and it contributes to APC binding CD201 is expressed on the surface of endothelial cells, which form the inner lining of blood vessels. CD201 has also been identified as hematopoietic stem cell (HSC) marker.

Function

The main function of CD201 is to enhance the activation of protein C. The binding of APC to EPCR on the endothelial cell surface facilitates its anticoagulant activity by inhibiting factors Va and VIIIa. Apart from its anticoagulant role, CD201 also participates in an anti-inflammatory signaling. CD201 has been shown to affect the production of inflammatory cytokines upon binding a coagulation factor VIIa.

Clinical significance

CD201 is gaining recognition as a marker in patients with acute infections as well as in patients with vascular diseases. Recently, CD201 has been studied in relationship with rheumatoid arthritis. In a recent study on emergency granulopoiesis, it has been observed that CD201 is highly expressed on lymphoid-biased HSCs under steady-state conditions. However, during emergency granulopoiesis, the loss of CD201 marked a transcriptional switch from a lymphoid to a myeloid identity in HSCs. These findings suggest that CD201 is involved in the regulation of the response to acute infection. As with many signaling molecules, the context of their effect matters. It has been mentioned above that CD201 has anti-inflammatory properties during coagulation. However, in a rheumatoid arthritis (RA) murine model it has been shown that CD201 knock-out (KO) mice had 40% lower arthritis incidence and 50% less disease severity compared to wild-type (WT) mice. CD201 KO mice also had significantly fewer Th1/Th17 cells in synovial tissues, which implies that CD201 may play a role in the regulation of immune cell populations involved in the pathogenesis of RA. The importance of CD201 as a clinical marker has been demonstrated in another study where decreased patient serum levels of CD201 have been associated with vascular dysfunctions.