| 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
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.
Publication Abstract from PubMed
Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC's anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC's cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC's anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.
Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.,Zhao XY, Wilmen A, Wang D, Wang X, Bauzon M, Kim JY, Linden L, Li L, Egner U, Marquardt T, Moosmayer D, Tebbe J, Gluck JM, Ellinger P, McLean K, Yuan S, Yegneswaran S, Jiang X, Evans V, Gu JM, Schneider D, Zhu Y, Xu Y, Mallari C, Hesslein A, Wang Y, Schmidt N, Gutberlet K, Ruehl-Fehlert C, Freyberger A, Hermiston T, Patel C, Sim D, Mosnier LO, Laux V Nat Commun. 2020 Jun 12;11(1):2992. doi: 10.1038/s41467-020-16720-9. PMID:32532974[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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:https://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
- ↑ Zhao XY, Wilmen A, Wang D, Wang X, Bauzon M, Kim JY, Linden L, Li L, Egner U, Marquardt T, Moosmayer D, Tebbe J, Glück JM, Ellinger P, McLean K, Yuan S, Yegneswaran S, Jiang X, Evans V, Gu JM, Schneider D, Zhu Y, Xu Y, Mallari C, Hesslein A, Wang Y, Schmidt N, Gutberlet K, Ruehl-Fehlert C, Freyberger A, Hermiston T, Patel C, Sim D, Mosnier LO, Laux V. Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia. Nat Commun. 2020 Jun 12;11(1):2992. PMID:32532974 doi:10.1038/s41467-020-16720-9
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