Protein S Explained

Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene.^{[1] [2]} Protein S plays a role in coagulation.

History

Protein S is named for Seattle, Washington, where it was originally discovered and purified^[3] by Earl Davie's group in 1977.^[4]

Structure

Protein S is partly homologous to other vitamin K-dependent plasma coagulation proteins, such as protein C and factors VII, IX, and X. Similar to them, it has a Gla domain and several EGF-like domains (four rather than two), but no serine protease domain. Instead, there is a large C-terminus domain that is homologous to plasma steroid hormone-binding proteins such as sex hormone-binding globulin and corticosteroid-binding globulin. It may play a role in the protein functions as either a cofactor for activated protein C (APC) or in binding C4BP.^{[5] [6]}

Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by thrombin. The Gla and EGF-like domains stay connected after the cleavage by a disulfide bond. However, protein S loses its function as an APC cofactor following either this cleavage or binding C4BP.^[7]

Function

The best characterized function of Protein S is its role in the anti coagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity.^[8]

Protein S binds to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to facilitate the removal of cells that are undergoing apoptosis, a form of structured cell death used by the body to remove unwanted or damaged cells. In healthy cells, an ATP (adenosine triphosphate)-dependent enzyme removes negatively charged phospholipids such as phosphatidyl serine from the outer leaflet of the cell membrane. An apoptotic cell (that is, one undergoing apoptosis) no longer actively manages the distribution of phospholipids in its outer membrane and hence begins to display negatively charged phospholipids on its exterior surface. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S binds to the negatively charged phospholipids and functions as a bridge between the apoptotic cell and the phagocyte. This bridging expedites phagocytosis and allows the cell to be removed without giving rise to inflammation or other signs of tissue damage.

Protein S does not bind to the nascent complement complex C5,6,7 to prevents it from inserting into a membrane. This is a different complement protein S AKA vitronectin made by the VTN gene, not to be confused with the coagulation protein S made by the PROS gene which this wiki page concerns.

Pathology

Mutations in the PROS1 gene can lead to Protein S deficiency which is a rare blood disorder which can lead to an increased risk of thrombosis.^{[9] [10]}

Interactions

Protein S has been shown to interact with Factor V.^{[11] [12]}

See also

• Hemostasis

Further reading

• Dahlbäck B . Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system . Thromb. Haemost. . 66 . 1 . 49–61 . 1991 . 1833851 . 10.1055/s-0038-1646373. 24929072 .
• Witt . I . Molekularbiologische Grundlagen und Diagnostik der hereditären Defekte von Antithrombin III, Protein C und Protein S . de . Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein c and protein S . Hamostaseologie . 22 . 2 . 57–66 . 2002 . 12193972 . 10.1055/s-0037-1619540. 58077740 .
• Rezende SM, Simmonds RE, Lane DA . Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex . Blood . 103 . 4 . 1192–201 . 2004 . 12907438 . 10.1182/blood-2003-05-1551 . 133028 . free .
• Dahlbäck B . The tale of protein S and C4b-binding protein, a story of affection . Thromb. Haemost. . 98 . 1 . 90–6 . 2007 . 17597997 . 10.1160/th07-04-0269. 18823655 .
• García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N . Molecular basis of protein S deficiency . Thromb. Haemost. . 98 . 3 . 543–56 . 2007 . 17849042 . 10.1160/th07-03-0199. 17274778 .
• Maillard C, Berruyer M, Serre CM, etal . Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts . Endocrinology . 130 . 3 . 1599–604 . 1992 . 10.1210/endo.130.3.1531628 . 1531628 .
• Griffin JH, Gruber A, Fernández JA . Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin . Blood . 79 . 12 . 3203–11 . 1992 . 1534488 . 10.1182/blood.V79.12.3203.bloodjournal79123203. 2024-04-10 . free .
• Guglielmone HA, Vides MA . A novel functional assay of protein C in human plasma and its comparison with amidolytic and anticoagulant assays . Thromb. Haemost. . 67 . 1 . 46–9 . 1992 . 1615482 . 10.1055/s-0038-1648377. 27769717 .
• Bertina RM, Ploos van Amstel HK, van Wijngaarden A, etal . Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460 . Blood . 76 . 3 . 538–48 . 1990 . 2143091 . 10.1182/blood.V76.3.538.538. free .
• Schmidel DK, Tatro AV, Phelps LG, etal . Organization of the human protein S genes . Biochemistry . 29 . 34 . 7845–52 . 1991 . 2148110 . 10.1021/bi00486a010 .
• Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM . Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution . Biochemistry . 29 . 34 . 7853–61 . 1991 . 2148111 . 10.1021/bi00486a011 .
• Allaart CF, Aronson DC, Ruys T, etal . Hereditary protein S deficiency in young adults with arterial occlusive disease . Thromb. Haemost. . 64 . 2 . 206–10 . 1991 . 2148653 .
• Ohlin AK, Landes G, Bourdon P, etal . Beta-hydroxyaspartic acid in the first epidermal growth factor-like domain of protein C. Its role in Ca2+ binding and biological activity . J. Biol. Chem. . 263 . 35 . 19240–8 . 1989 . 10.1016/S0021-9258(18)37415-5 . 2461936 . free .
• Schwarz HP, Heeb MJ, Lottenberg R, etal . Familial protein S deficiency with a variant protein S molecule in plasma and platelets . Blood . 74 . 1 . 213–21 . 1989 . 2526663 . 10.1182/blood.V74.1.213.213. free .
• Ploos van Amstel HK, van der Zanden AL, Reitsma PH, Bertina RM . Human protein S cDNA encodes Phe-16 and Tyr 222 in consensus sequences for the post-translational processing . FEBS Lett. . 222 . 1 . 186–90 . 1987 . 2820795 . 10.1016/0014-5793(87)80217-X . 46365357 . free .
• Dahlbäck B, Lundwall A, Stenflo J . Primary structure of bovine vitamin K-dependent protein S . Proc. Natl. Acad. Sci. U.S.A. . 83 . 12 . 4199–203 . 1986 . 2940598 . 10.1073/pnas.83.12.4199 . 323699 . 1986PNAS...83.4199D . free .
• Lundwall A, Dackowski W, Cohen E, etal . Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation . Proc. Natl. Acad. Sci. U.S.A. . 83 . 18 . 6716–20 . 1986 . 2944113 . 10.1073/pnas.83.18.6716 . 386580 . 1986PNAS...83.6716L . free .
• Engesser L, Broekmans AW, Briët E, etal . Hereditary protein S deficiency: clinical manifestations . Ann. Intern. Med. . 106 . 5 . 677–82 . 1987 . 2952034 . 10.7326/0003-4819-106-5-677 .
• Watkins PC, Eddy R, Fukushima Y, etal . The gene for protein S maps near the centromere of human chromosome 3 . Blood . 71 . 1 . 238–41 . 1988 . 2961379 . 10.1182/blood.V71.1.238.238.

Notes and References

1. Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlbäck B, Stenflo J, Wydro R . Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation . Proc. Natl. Acad. Sci. U.S.A. . 83 . 18 . 6716–20 . September 1986 . 2944113 . 386580 . 10.1073/pnas.83.18.6716. 1986PNAS...83.6716L . free .
2. Long GL, Marshall A, Gardner JC, Naylor SL . Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively . Somat. Cell Mol. Genet. . 14 . 1 . 93–8 . January 1988 . 2829367 . 10.1007/BF01535052. Vitamin K-dependent protein . 31236887 .
3. Web site: Protein S deficiency. UpToDate. May 10, 2017.
4. Book: Kaushansky . K. Lichtman . M. Prchal . J. Levi . M. Press . O. Burns . L. Caligiuri . M. Williams Hematology . 2015 . McGraw-Hill . 1926.
5. Stenflo J . Contributions of Gla and EGF-like domains to the function of vitamin K-dependent coagulation factors . Critical Reviews in Eukaryotic Gene Expression . 9 . 1 . 59–88 . 1999 . 10200912 . 10.1615/CritRevEukaryotGeneExpr.v9.i1.50.
6. Rosner W . Plasma steroid-binding proteins . Endocrinology and Metabolism Clinics of North America . 20 . 4 . 697–720 . Dec 1991 . 1778174 . 10.1016/S0889-8529(18)30240-8.
7. Dahlbäck B, Lundwall A, Stenflo J . Primary structure of bovine vitamin K-dependent protein S . Proceedings of the National Academy of Sciences . 83 . 12 . 4199–203 . Jun 1986 . 2940598 . 10.1073/pnas.83.12.4199 . 323699. 1986PNAS...83.4199D . free .
8. Castoldi E, Hackeng TM . Regulation of coagulation by protein S . Curr. Opin. Hematol. . 15 . 5 . 529–36 . September 2008 . 18695379 . 10.1097/MOH.0b013e328309ec97 . 11522770 .
9. Beauchamp NJ, Dykes AC, Parikh N, Campbell Tait R, Daly ME . The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population . Br. J. Haematol. . 125 . 5 . 647–54 . June 2004 . 15147381 . 10.1111/j.1365-2141.2004.04961.x . 705661 .
10. García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N . Molecular basis of protein S deficiency . Thromb. Haemost. . 98 . 3 . 543–56 . September 2007 . 17849042 . 10.1160/th07-03-0199. 17274778 .
11. 10.1074/jbc.274.51.36187 . Heeb . M J . Kojima Y . Rosing J . Tans G . Griffin J H . Dec 1999 . C-terminal residues 621-635 of protein S are essential for binding to factor Va . J. Biol. Chem. . 274 . 51 . 36187–92 . UNITED STATES. 0021-9258. 10593904 . 45995946 . free .
12. Heeb . M J . Mesters R M . Tans G . Rosing J . Griffin J H . Feb 1993 . Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C . J. Biol. Chem. . 268 . 4 . 2872–7 . UNITED STATES. 10.1016/S0021-9258(18)53854-0 . 0021-9258. 8428962 . free .