Endothelial protein C receptor
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| Aliases | PROCR, CCCA, CCD41, EPCR, protein C receptor | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 600646; MGI: 104596; HomoloGene: 4670; GeneCards: PROCR; OMA:PROCR - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[5][6][7] 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.[8]
Structure
[edit]EPCR protein is an N-glycosylated type I membrane protein that enhances the activation of protein C.[7] 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.[8] 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[9]
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.[10][11]
Function
[edit]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.[12]
Clinical significance
[edit]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.[13] 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.[14]
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.[15]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000101000 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027611 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Fukudome K, Esmon CT (Nov 1994). "Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor". J Biol Chem. 269 (42): 26486–91. doi:10.1016/S0021-9258(18)47220-1. PMID 7929370.
- ^ Rothbarth K, Dabaghian AR, Stammer H, Werner D (Oct 1999). "One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR)". FEBS Lett. 458 (1): 77–80. doi:10.1016/S0014-5793(99)01074-1. PMID 10518938. S2CID 25425851.
- ^ a b "Entrez Gene: PROCR protein C receptor, endothelial (EPCR)".
- ^ a b Esmon CT (May 2004). "Structure and functions of the endothelial cell protein C receptor". Critical Care Medicine. 32 (Supplement): S298–S301. doi:10.1097/01.CCM.0000126128.64614.81. ISSN 0090-3493. PMID 15118534.
- ^ Esmon CT (May 2004). "Structure and functions of the endothelial cell protein C receptor". Critical Care Medicine. 32 (5 Suppl): S298-301. doi:10.1097/01.CCM.0000126128.64614.81. PMID 15118534.
- ^ Vazquez SE, Inlay MA, Serwold T (Jul 2015). "CD201 and CD27 identify hematopoietic stem and progenitor cells across multiple murine strains independently of Kit and Sca-1". Experimental Hematology. 43 (7): 578–585. doi:10.1016/j.exphem.2015.04.001. PMC 4480781. PMID 25892186.
- ^ Balazs AB, Fabian AJ, Esmon CT, Mulligan RC (2006-03-15). "Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow". Blood. 107 (6): 2317–2321. doi:10.1182/blood-2005-06-2249. ISSN 0006-4971. PMC 1895725. PMID 16304059.
- ^ Kondreddy V, Wang J, Keshava S, Esmon CT, Rao LV, Pendurthi UR (2018-05-24). "Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1". Blood. 131 (21): 2379–2392. doi:10.1182/blood-2017-10-813527. ISSN 1528-0020. PMC 5969379. PMID 29669778.
- ^ Vanickova K, Milosevic M, Ribeiro Bas I, Burocziova M, Yokota A, Danek P, Grusanovic S, Chiliński M, Plewczynski D, Rohlena J, Hirai H, Rohlenova K, Alberich-Jorda M (2023-12-01). "Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis". The EMBO Journal. 42 (23): e113527. doi:10.15252/embj.2023113527. ISSN 1460-2075. PMC 10690458. PMID 37846891.
- ^ Xue M, Lin H, Liang HP, Bereza-Malcolm L, Lynch T, Sinnathurai P, Weiler H, Jackson C, March L (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. doi:10.1093/rheumatology/kead230. ISSN 1462-0332. PMC 10834933. PMID 37228024.
- ^ Krug J, Bochenek ML, Gogiraju R, Laubert-Reh D, Lackner KJ, Münzel T, Wild PS, Espinola-Klein C, Schäfer K (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. doi:10.3390/biomedicines11092459. ISSN 2227-9059. PMC 10526050. PMID 37760900.
Further reading
[edit]- Esmon CT (2004). "Coagulation and inflammation". J. Endotoxin Res. 9 (3): 192–8. doi:10.1179/096805103125001603. PMID 12831462.
- Ruf W, Dorfleutner A, Riewald M (2003). "Specificity of coagulation factor signaling". J. Thromb. Haemost. 1 (7): 1495–503. doi:10.1046/j.1538-7836.2003.00300.x. PMID 12871285. S2CID 22565813.
- Van de Wouwer M, Collen D, Conway EM (2005). "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1374–83. doi:10.1161/01.ATV.0000134298.25489.92. PMID 15178554.
- Medina P, Navarro S, Estellés A, España F (2007). "Polymorphisms in the endothelial protein C receptor gene and thrombophilia". Thromb. Haemost. 98 (3): 564–9. doi:10.1160/th07-01-0071. PMID 17849044. S2CID 3646665.
- Raheja KK (1977). "Nursing in transition". Nursing Forum. 15 (4): 413–7. doi:10.1111/j.1744-6198.1976.tb01065.x. PMID 1051893.
- Laszik Z, Mitro A, Taylor FB, et al. (1998). "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. doi:10.1161/01.cir.96.10.3633. PMID 9396465.
- Ye X, Fukudome K, Tsuneyoshi N, et al. (1999). "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. doi:10.1006/bbrc.1999.0846. PMID 10364477.
- Simmonds RE, Lane DA (1999). "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. doi:10.1182/blood.V94.2.632. PMID 10397730.
- Hayashi T, Nakamura H, Okada A, et al. (1999). "Organization and chromosomal localization of the human endothelial protein C receptor gene". Gene. 238 (2): 367–73. doi:10.1016/S0378-1119(99)00360-1. PMID 10570964.
- Liaw PC, Neuenschwander PF, Smirnov MD, Esmon CT (2000). "Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function". J. Biol. Chem. 275 (8): 5447–52. doi:10.1074/jbc.275.8.5447. PMID 10681521.
- Xu J, Qu D, Esmon NL, Esmon CT (2000). "Metalloproteolytic release of endothelial cell protein C receptor". J. Biol. Chem. 275 (8): 6038–44. doi:10.1074/jbc.275.8.6038. PMID 10681599.
- Liaw PC, Mather T, Oganesyan N, et al. (2001). "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. doi:10.1074/jbc.M010572200. PMID 11099506.
- Biguzzi E, Merati G, Liaw PC, et al. (2002). "A 23bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function". Thromb. Haemost. 86 (4): 945–8. PMID 11686350.
- Galligan L, Livingstone W, Volkov Y, et al. (2001). "Characterization of protein C receptor expression in monocytes". Br. J. Haematol. 115 (2): 408–14. doi:10.1046/j.1365-2141.2001.03187.x. PMID 11703343. S2CID 6186108.
- von Depka M, Czwalinna A, Eisert R, et al. (2002). "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. PMID 11776299.
- Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature. 414 (6866): 865–71. Bibcode:2001Natur.414..865D. doi:10.1038/414865a. PMID 11780052.
- Oganesyan V, Oganesyan N, Terzyan S, et al. (2002). "The crystal structure of the endothelial protein C receptor and a bound phospholipid". J. Biol. Chem. 277 (28): 24851–4. doi:10.1074/jbc.C200163200. PMID 12034704.
- Riewald M, Petrovan RJ, Donner A, et al. (2002). "Activation of endothelial cell protease activated receptor 1 by the protein C pathway". Science. 296 (5574): 1880–2. Bibcode:2002Sci...296.1880R. doi:10.1126/science.1071699. PMID 12052963. S2CID 43006410.
External links
[edit]- Overview of all the structural information available in the PDB for UniProt: Q9UNN8 (Endothelial protein C receptor) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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