Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. 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 PROS1gene. In 1979, researchers in Seattle, Washington first discovered protein S and arbitrarily named it after the city of its discovery.
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.
Protein S can bind to negatively charged phospholipids via the carboxylated GLA domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis. Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells which are apoptotic (i.e. in the process of apoptosis) no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP (Adenosine triphosphate)-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring.
^Long GL, Marshall A, Gardner JC, Naylor SL (January 1988). "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. doi:10.1007/BF01535052. PMID2829367.
^Di Scipio RG, Hermodson MA, Yates SG, Davie EW (February 1977). "A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S". Biochemistry16 (4): 698–706. doi:10.1021/bi00623a022. PMID836809.
^DiScipio RG, Davie EW (March 1979). "Characterization of protein S, a gamma-carboxyglutamic acid containing protein from bovine and human plasma". Biochemistry18 (5): 899–904. doi:10.1021/bi00572a026. PMID420821.
^Beauchamp NJ, Dykes AC, Parikh N, Campbell Tait R, Daly ME (June 2004). "The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population". Br. J. Haematol.125 (5): 647–54. doi:10.1111/j.1365-2141.2004.04961.x. PMID15147381.
^García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N (September 2007). "Molecular basis of protein S deficiency". Thromb. Haemost.98 (3): 543–56. PMID17849042.
^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. (UNITED STATES) 274 (51): 36187–92. doi:10.1074/jbc.274.51.36187. ISSN0021-9258. PMID10593904.Cite uses deprecated parameters (help)
^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. (UNITED STATES) 268 (4): 2872–7. ISSN0021-9258. PMID8428962.Cite uses deprecated parameters (help)
Rezende SM, Simmonds RE, Lane DA (2004). "Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex". Blood103 (4): 1192–201. doi:10.1182/blood-2003-05-1551. PMID12907438.
Dahlbäck B (2007). "The tale of protein S and C4b-binding protein, a story of affection". Thromb. Haemost.98 (1): 90–6. PMID17597997.
García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N (2007). "Molecular basis of protein S deficiency". Thromb. Haemost.98 (3): 543–56. PMID17849042.
Maillard C, Berruyer M, Serre CM, et al. (1992). "Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts". Endocrinology130 (3): 1599–604. doi:10.1210/en.130.3.1599. PMID1531628.
Griffin JH, Gruber A, Fernández JA (1992). "Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin". Blood79 (12): 3203–11. PMID1534488.
Guglielmone HA, Vides MA (1992). "A novel functional assay of protein C in human plasma and its comparison with amidolytic and anticoagulant assays". Thromb. Haemost.67 (1): 46–9. PMID1615482.
Bertina RM, Ploos van Amstel HK, van Wijngaarden A, et al. (1990). "Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460". Blood76 (3): 538–48. PMID2143091.
Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM (1991). "Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution". Biochemistry29 (34): 7853–61. doi:10.1021/bi00486a011. PMID2148111.
Allaart CF, Aronson DC, Ruys T, et al. (1991). "Hereditary protein S deficiency in young adults with arterial occlusive disease". Thromb. Haemost.64 (2): 206–10. PMID2148653.
Ohlin AK, Landes G, Bourdon P, et al. (1989). "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. PMID2461936.
Schwarz HP, Heeb MJ, Lottenberg R, et al. (1989). "Familial protein S deficiency with a variant protein S molecule in plasma and platelets". Blood74 (1): 213–21. PMID2526663.
Ploos van Amstel HK, van der Zanden AL, Reitsma PH, Bertina RM (1987). "Human protein S cDNA encodes Phe-16 and Tyr 222 in consensus sequences for the post-translational processing". FEBS Lett.222 (1): 186–90. doi:10.1016/0014-5793(87)80217-X. PMID2820795.