Endothelial protein C receptor explained

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.^{[1] [2] [3]} 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.^[4]

Structure

EPCR protein is an N-glycosylated type I membrane protein that enhances the activation of protein C.^[3] 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^[5]

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.^{[6] [7]}

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.^[8]

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.^[9] 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.^[10]

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.^[11]

Further reading

• Esmon CT . Coagulation and inflammation. . J. Endotoxin Res. . 9 . 3 . 192–8 . 2004 . 12831462 . 10.1179/096805103125001603 .
• Ruf W, Dorfleutner A, Riewald M . Specificity of coagulation factor signaling. . J. Thromb. Haemost. . 1 . 7 . 1495–503 . 2003 . 12871285 . 10.1046/j.1538-7836.2003.00300.x . 22565813 .
• Van de Wouwer M, Collen D, Conway EM . Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. . Arterioscler. Thromb. Vasc. Biol. . 24 . 8 . 1374–83 . 2005 . 15178554 . 10.1161/01.ATV.0000134298.25489.92 .
• Medina P, Navarro S, Estellés A, España F . Polymorphisms in the endothelial protein C receptor gene and thrombophilia. . Thromb. Haemost. . 98 . 3 . 564–9 . 2007 . 17849044 . 10.1160/th07-01-0071. 3646665 .
• Raheja KK . Nursing in transition. . Nursing Forum . 15 . 4 . 413–7 . 1977 . 1051893 . 10.1111/j.1744-6198.1976.tb01065.x . free .
• Laszik Z, Mitro A, Taylor FB . Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. . Circulation . 96 . 10 . 3633–40 . 1998 . 9396465 . 10.1161/01.cir.96.10.3633. etal.
• Ye X, Fukudome K, Tsuneyoshi N . The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. . Biochem. Biophys. Res. Commun. . 259 . 3 . 671–7 . 1999 . 10364477 . 10.1006/bbrc.1999.0846 . etal.
• Simmonds RE, Lane DA . Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains. . Blood . 94 . 2 . 632–41 . 1999 . 10397730 . 10.1182/blood.V94.2.632.
• Hayashi T, Nakamura H, Okada A . Organization and chromosomal localization of the human endothelial protein C receptor gene. . Gene . 238 . 2 . 367–73 . 1999 . 10570964 . 10.1016/S0378-1119(99)00360-1 . etal.
• Liaw PC, Neuenschwander PF, Smirnov MD, Esmon CT . Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. . J. Biol. Chem. . 275 . 8 . 5447–52 . 2000 . 10681521 . 10.1074/jbc.275.8.5447 . free .
• Xu J, Qu D, Esmon NL, Esmon CT . Metalloproteolytic release of endothelial cell protein C receptor. . J. Biol. Chem. . 275 . 8 . 6038–44 . 2000 . 10681599 . 10.1074/jbc.275.8.6038 . free .
• Liaw PC, Mather T, Oganesyan N . Identification of the protein C/activated protein C binding sites on the endothelial cell protein C receptor. Implications for a novel mode of ligand recognition by a major histocompatibility complex class 1-type receptor. . J. Biol. Chem. . 276 . 11 . 8364–70 . 2001 . 11099506 . 10.1074/jbc.M010572200 . etal. free .
• Biguzzi E, Merati G, Liaw PC . A 23bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function. . Thromb. Haemost. . 86 . 4 . 945–8 . 2002 . 11686350 . etal.
• Galligan L, Livingstone W, Volkov Y . Characterization of protein C receptor expression in monocytes. . Br. J. Haematol. . 115 . 2 . 408–14 . 2001 . 11703343 . 10.1046/j.1365-2141.2001.03187.x . 6186108 . etal.
• von Depka M, Czwalinna A, Eisert R . Prevalence of a 23bp insertion in exon 3 of the endothelial cell protein C receptor gene in venous thrombophilia. . Thromb. Haemost. . 86 . 6 . 1360–2 . 2002 . 11776299 . etal.
• Deloukas P, Matthews LH, Ashurst J . The DNA sequence and comparative analysis of human chromosome 20. . Nature . 414 . 6866 . 865–71 . 2002 . 11780052 . 10.1038/414865a . 2001Natur.414..865D . etal. free .
• Oganesyan V, Oganesyan N, Terzyan S . The crystal structure of the endothelial protein C receptor and a bound phospholipid. . J. Biol. Chem. . 277 . 28 . 24851–4 . 2002 . 12034704 . 10.1074/jbc.C200163200 . etal. free .
• Riewald M, Petrovan RJ, Donner A . Activation of endothelial cell protease activated receptor 1 by the protein C pathway. . Science . 296 . 5574 . 1880–2 . 2002 . 12052963 . 10.1126/science.1071699 . 2002Sci...296.1880R . 43006410 . etal.

Notes and References

1. Fukudome K, Esmon CT . Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor . J Biol Chem . 269 . 42 . 26486–91 . Nov 1994 . 10.1016/S0021-9258(18)47220-1 . 7929370 . free .
2. Rothbarth K, Dabaghian AR, Stammer H, Werner D . One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR) . FEBS Lett . 458 . 1 . 77–80 . Oct 1999 . 10518938 . 10.1016/S0014-5793(99)01074-1 . 25425851 .
3. Web site: Entrez Gene: PROCR protein C receptor, endothelial (EPCR).
4. Esmon . Charles T. . May 2004 . Structure and functions of the endothelial cell protein C receptor . Critical Care Medicine . en . 32 . Supplement . S298–S301 . 10.1097/01.CCM.0000126128.64614.81 . 15118534 . 0090-3493.
5. Esmon CT . Structure and functions of the endothelial cell protein C receptor . Critical Care Medicine . 32 . 5 Suppl . S298-301 . May 2004 . 15118534 . 10.1097/01.CCM.0000126128.64614.81 .
6. Vazquez . Sara E. . Inlay . Matthew A. . Serwold . Thomas . Jul 2015 . CD201 and CD27 identify hematopoietic stem and progenitor cells across multiple murine strains independently of Kit and Sca-1 . Experimental Hematology . en . 43 . 7 . 578–585 . 10.1016/j.exphem.2015.04.001 . 4480781 . 25892186.
7. Balazs . Alejandro B. . Fabian . Attila J. . Esmon . Charles T. . Mulligan . Richard C. . 2006-03-15 . Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow . Blood . 107 . 6 . 2317–2321 . 10.1182/blood-2005-06-2249 . 0006-4971 . 1895725 . 16304059.
8. Kondreddy . Vijay . Wang . Jue . Keshava . Shiva . Esmon . Charles T. . Rao . L. Vijaya Mohan . Pendurthi . Usha R. . 2018-05-24 . Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1 . Blood . 131 . 21 . 2379–2392 . 10.1182/blood-2017-10-813527 . 1528-0020 . 5969379 . 29669778.
9. Vanickova . Karolina . Milosevic . Mirko . Ribeiro Bas . Irina . Burocziova . Monika . Yokota . Asumi . Danek . Petr . Grusanovic . Srdjan . Chiliński . Mateusz . Plewczynski . Dariusz . Rohlena . Jakub . Hirai . Hideyo . Rohlenova . Katerina . Alberich-Jorda . Meritxell . 2023-12-01 . Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis . The EMBO Journal . 42 . 23 . e113527 . 10.15252/embj.2023113527 . 1460-2075 . 10690458 . 37846891.
10. Xue . Meilang . Lin . Haiyan . Liang . Hai Po Helena . Bereza-Malcolm . Lara . Lynch . Tom . Sinnathurai . Premarani . Weiler . Hartmut . Jackson . Christopher . March . Lyn . 2024-02-01 . EPCR deficiency ameliorates inflammatory arthritis in mice by suppressing the activation and migration of T cells and dendritic cells . Rheumatology . 63 . 2 . 571–580 . 10.1093/rheumatology/kead230 . 1462-0332 . 10834933 . 37228024.
11. Krug . Janina . Bochenek . Magdalena L. . Gogiraju . Rajinikanth . Laubert-Reh . Dagmar . Lackner . Karl J. . Münzel . Thomas . Wild . Philipp S. . Espinola-Klein . Christine . Schäfer . Katrin . 2023-09-04 . Circulating Soluble EPCR Levels Are Reduced in Patients with Ischemic Peripheral Artery Disease and Associated with Markers of Endothelial and Vascular Function . Biomedicines . 11 . 9 . 2459 . 10.3390/biomedicines11092459 . free . 2227-9059 . 10526050 . 37760900.