| Structural highlights
Disease
[PROC_HUMAN] Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare.
Function
[EPCR_HUMAN] Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation. [PROC_HUMAN] Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The endothelial cell protein C receptor (EPCR) shares approximately 20% sequence identity with the major histocompatibility complex class 1/CD1 family of molecules, accelerates the thrombin-thrombomodulin-dependent generation of activated protein C, a natural anticoagulant, binds to activated neutrophils, and can undergo translocation from the plasma membrane to the nucleus. Blocking protein C/activated protein C binding to the receptor inhibits not only protein C activation but the ability of the host to respond appropriately to bacterial challenge, exacerbating both the coagulant and inflammatory responses. To understand how EPCR accomplishes these multiple tasks, we solved the crystal structure of EPCR alone and in complex with the phospholipid binding domain of protein C. The structures were strikingly similar to CD1d. A tightly bound phospholipid resides in the groove typically involved in antigen presentation. The protein C binding site is outside this conserved groove and is distal from the membrane-spanning domain. Extraction of the lipid resulted in loss of protein C binding, which could be restored by lipid reconstitution. CD1d augments the immune response by presenting glycolipid antigens. The EPCR structure is a model for how CD1d binds lipids and further suggests additional potential functions for EPCR in immune regulation, possibly including the anti-phospholipid syndrome.
The crystal structure of the endothelial protein C receptor and a bound phospholipid.,Oganesyan V, Oganesyan N, Terzyan S, Qu D, Dauter Z, Esmon NL, Esmon CT J Biol Chem. 2002 Jul 12;277(28):24851-4. Epub 2002 May 28. PMID:12034704[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Miyata T, Zheng YZ, Sakata T, Kato H. Protein C Osaka 10 with aberrant propeptide processing: loss of anticoagulant activity due to an amino acid substitution in the protein C precursor. Thromb Haemost. 1995 Oct;74(4):1003-8. PMID:8560401
- ↑ Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vicente V, Mannucci PM, Bertina R, Peschle C, et al.. Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene. Proc Natl Acad Sci U S A. 1987 May;84(9):2829-32. PMID:2437584
- ↑ Grundy C, Chitolie A, Talbot S, Bevan D, Kakkar V, Cooper DN. Protein C London 1: recurrent mutation at Arg 169 (CGG----TGG) in the protein C gene causing thrombosis. Nucleic Acids Res. 1989 Dec 25;17(24):10513. PMID:2602169
- ↑ Reitsma PH, Poort SR, Allaart CF, Briet E, Bertina RM. The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood. 1991 Aug 15;78(4):890-4. PMID:1868249
- ↑ Bovill EG, Tomczak JA, Grant B, Bhushan F, Pillemer E, Rainville IR, Long GL. Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations. Blood. 1992 Mar 15;79(6):1456-65. PMID:1347706
- ↑ Grundy CB, Schulman S, Tengborn L, Kakkar VV, Cooper DN. Two different missense mutations at Arg 178 of the protein C (PROC) gene causing recurrent venous thrombosis. Hum Genet. 1992 Aug;89(6):685-6. PMID:1511989
- ↑ Gandrille S, Vidaud M, Aiach M, Alhenc-Gelas M, Fischer AM, Gouault-Heilman M, Toulon P, Fiessinger JN, Goossens M. Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis. Hum Mutat. 1992;1(6):491-500. PMID:1301959 doi:http://dx.doi.org/10.1002/humu.1380010607
- ↑ Millar DS, Grundy CB, Bignell P, Moffat EH, Martin R, Kakkar VV, Cooper DN. A Gla domain mutation (Arg 15-->Trp) in the protein C (PROC) gene causing type 2 protein C deficiency and recurrent venous thrombosis. Blood Coagul Fibrinolysis. 1993 Apr;4(2):345-7. PMID:8499568
- ↑ Tsay W, Greengard JS, Montgomery RR, McPherson RA, Fucci JC, Koerper MA, Coughlin J, Griffin JH. Genetic mutations in ten unrelated American patients with symptomatic type 1 protein C deficiency. Blood Coagul Fibrinolysis. 1993 Oct;4(5):791-6. PMID:8292730
- ↑ Marchetti G, Patracchini P, Gemmati D, Castaman G, Rodeghiero F, Wacey A, Cooper DN, Tuddenham EG, Bernardi F. Symptomatic type II protein C deficiency caused by a missense mutation (Gly 381-->Ser) in the substrate-binding pocket. Br J Haematol. 1993 Jun;84(2):285-9. PMID:8398832
- ↑ Zheng YZ, Sakata T, Matsusue T, Umeyama H, Kato H, Miyata T. Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling. Blood Coagul Fibrinolysis. 1994 Oct;5(5):687-96. PMID:7865674
- ↑ Lind B, Schwartz M, Thorsen S. Six different point mutations in seven Danish families with symptomatic protein C deficiency. Thromb Haemost. 1995 Feb;73(2):186-93. PMID:7792728
- ↑ Ireland HA, Boisclair MD, Taylor J, Thompson E, Thein SL, Girolami A, De Caterina M, Scopacasa F, De Stefano V, Leone G, Finazzi G, Cohen H, Lane DA. Two novel (R(-11)C; T394D) and two repeat missense mutations in the protein C gene associated with venous thrombosis in six kindreds. Hum Mutat. 1996;7(2):176-9. PMID:8829639 doi:<176::AID-HUMU16>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)7:2<176::AID-HUMU16>3.0.CO;2-#
- ↑ Couture P, Demers C, Morissette J, Delage R, Jomphe M, Couture L, Simard J. Type I protein C deficiency in French Canadians: evidence of a founder effect and association of specific protein C gene mutations with plasma protein C levels. Thromb Haemost. 1998 Oct;80(4):551-6. PMID:9798967
- ↑ Oganesyan V, Oganesyan N, Terzyan S, Qu D, Dauter Z, Esmon NL, Esmon CT. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem. 2002 Jul 12;277(28):24851-4. Epub 2002 May 28. PMID:12034704 doi:http://dx.doi.org/10.1074/jbc.C200163200
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