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Protein S (alpha)

PDB rendering based on 1z6c.
Available structures
Symbols PROS1; PSA; PROS; PS 26; PS21; PS22; PS23; PS24; PS25; Protein S; protein Sa
External IDs OMIM176880 MGI1095733 HomoloGene264 GeneCards: PROS1 Gene
RNA expression pattern
PBB GE PROS1 207808 s at tn.png
More reference expression data
Species Human Mouse
Entrez 5627 19128
Ensembl ENSG00000184500 ENSMUSG00000022912
UniProt P07225 Q3TR66
RefSeq (mRNA) NM_000313 NM_011173
RefSeq (protein) NP_000304 NP_035303
Location (UCSC) Chr 3:
95.07 - 95.18 Mb
Chr 16:
62.8 - 62.87 Mb
PubMed search [1] [2]

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. In humans, protein S is encoded by the PROS1 gene.[1][2]



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.[3]

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 (ie. 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.


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.[4][5]


Protein S has been shown to interact with Factor V.[6][7]

See also


  1. ^ Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlbäck B, Stenflo J, Wydro R (September 1986). "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. PMID 2944113. 
  2. ^ 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. PMID 2829367. 
  3. ^ Castoldi E, Hackeng TM (September 2008). "Regulation of coagulation by protein S". Curr. Opin. Hematol. 15 (5): 529–36. doi:10.1097/MOH.0b013e328309ec97. PMID 18695379. 
  4. ^ 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. PMID 15147381. 
  5. ^ 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. PMID 17849042. 
  6. ^ 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. ISSN 0021-9258. PMID 10593904. 
  7. ^ 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. ISSN 0021-9258. PMID 8428962. 

Further reading

  • Dahlbäck B (1991). "Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system". Thromb. Haemost. 66 (1): 49–61. PMID 1833851. 
  • Witt I (2002). "[Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein c and protein S]". Hamostaseologie 22 (2): 14–24. doi:10.1267/Hamo02020057 (inactive 2008-06-22). PMID 12193972. 
  • Rezende SM, Simmonds RE, Lane DA (2004). "Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex". Blood 103 (4): 1192–201. doi:10.1182/blood-2003-05-1551. PMID 12907438. 
  • Dahlbäck B (2007). "The tale of protein S and C4b-binding protein, a story of affection". Thromb. Haemost. 98 (1): 90–6. PMID 17597997. 
  • García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N (2007). "Molecular basis of protein S deficiency". Thromb. Haemost. 98 (3): 543–56. PMID 17849042. 
  • 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". Endocrinology 130 (3): 1599–604. doi:10.1210/en.130.3.1599. PMID 1531628. 
  • 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". Blood 79 (12): 3203–11. PMID 1534488. 
  • 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. PMID 1615482. 
  • 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". Blood 76 (3): 538–48. PMID 2143091. 
  • Schmidel DK, Tatro AV, Phelps LG, et al. (1991). "Organization of the human protein S genes". Biochemistry 29 (34): 7845–52. doi:10.1021/bi00486a010. PMID 2148110. 
  • 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". Biochemistry 29 (34): 7853–61. doi:10.1021/bi00486a011. PMID 2148111. 
  • 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. PMID 2148653. 
  • 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. PMID 2461936. 
  • Schwarz HP, Heeb MJ, Lottenberg R, et al. (1989). "Familial protein S deficiency with a variant protein S molecule in plasma and platelets". Blood 74 (1): 213–21. PMID 2526663. 
  • 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. PMID 2820795. 
  • Dahlbäck B, Lundwall A, Stenflo J (1986). "Primary structure of bovine vitamin K-dependent protein S". Proc. Natl. Acad. Sci. U.S.A. 83 (12): 4199–203. doi:10.1073/pnas.83.12.4199. PMID 2940598. 
  • Lundwall A, Dackowski W, Cohen E, et al. (1986). "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. doi:10.1073/pnas.83.18.6716. PMID 2944113. 
  • Engesser L, Broekmans AW, Briët E, et al. (1987). "Hereditary protein S deficiency: clinical manifestations". Ann. Intern. Med. 106 (5): 677–82. PMID 2952034. 
  • Watkins PC, Eddy R, Fukushima Y, et al. (1988). "The gene for protein S maps near the centromere of human chromosome 3". Blood 71 (1): 238–41. PMID 2961379. 


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