{{Short description|Vitamin K-dependent plasma glycoprotein synthesized in the liver}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{more footnotes|date=August 2013}} {{Infobox_gene}} '''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.<ref name="pmid2944113">{{cite journal | vauthors = Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlbäck B, Stenflo J, Wydro R | title = Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 18 | pages = 6716–6720 | date = September 1986 | pmid = 2944113 | pmc = 386580 | doi = 10.1073/pnas.83.18.6716 | doi-access = free | bibcode = 1986PNAS...83.6716L }}</ref><ref name="pmid2829367">{{cite journal | vauthors = Long GL, Marshall A, Gardner JC, Naylor SL | title = Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively | journal = Somatic Cell and Molecular Genetics | volume = 14 | issue = 1 | pages = 93–98 | date = January 1988 | pmid = 2829367 | doi = 10.1007/BF01535052 | s2cid = 31236887 | title-link = Vitamin K-dependent protein }}</ref> Protein S plays a role in coagulation.

==History== Protein S is named for Seattle, Washington, where it was originally discovered and purified<ref>{{cite web | vauthors = Bauer KA | date = February 2025 | veditors = Leung LL, Tirnauer JS |title=Protein S deficiency|url=https://www.uptodate.com/contents/protein-s-deficiency?source=machineLearning&search=protein%20s%20deficiency%20adult&selectedTitle=1~110&sectionRank=1&anchor=H3#H3|website=UpToDate|access-date=May 10, 2017}}</ref> by Earl Davie's group in 1977.<ref>{{cite book | vauthors = Kaushansky K, Lichtman M, Prchal J, Levi M, Press O, Burns L, Caligiuri M |title=Williams Hematology |date=2015 |publisher=McGraw-Hill |page=1926}}</ref>

== 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.<ref>{{cite journal | vauthors = Stenflo J | title = Contributions of Gla and EGF-like domains to the function of vitamin K-dependent coagulation factors | journal = Critical Reviews in Eukaryotic Gene Expression | volume = 9 | issue = 1 | pages = 59–88 | date = 1999 | pmid = 10200912 | doi = 10.1615/CritRevEukaryotGeneExpr.v9.i1.50 }}</ref><ref>{{cite journal | vauthors = Rosner W | title = Plasma steroid-binding proteins | journal = Endocrinology and Metabolism Clinics of North America | volume = 20 | issue = 4 | pages = 697–720 | date = December 1991 | pmid = 1778174 | doi = 10.1016/S0889-8529(18)30240-8 }}</ref>

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.<ref>{{cite journal | vauthors = Dahlbäck B, Lundwall A, Stenflo J | title = Primary structure of bovine vitamin K-dependent protein S | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 12 | pages = 4199–4203 | date = June 1986 | pmid = 2940598 | pmc = 323699 | doi = 10.1073/pnas.83.12.4199 | doi-access = free | bibcode = 1986PNAS...83.4199D }}</ref>

== 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.<ref name="pmid18695379">{{cite journal | vauthors = Castoldi E, Hackeng TM | title = Regulation of coagulation by protein S | journal = Current Opinion in Hematology | volume = 15 | issue = 5 | pages = 529–536 | date = September 2008 | pmid = 18695379 | doi = 10.1097/MOH.0b013e328309ec97 | s2cid = 11522770 }}</ref>

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 prevent 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.<ref name="pmid15147381">{{cite journal | vauthors = Beauchamp NJ, Dykes AC, Parikh N, Campbell Tait R, Daly ME | title = The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population | journal = British Journal of Haematology | volume = 125 | issue = 5 | pages = 647–654 | date = June 2004 | pmid = 15147381 | doi = 10.1111/j.1365-2141.2004.04961.x | s2cid = 705661 }}</ref><ref name="pmid17849042">{{cite journal | vauthors = García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N | title = Molecular basis of protein S deficiency | journal = Thrombosis and Haemostasis | volume = 98 | issue = 3 | pages = 543–556 | date = September 2007 | pmid = 17849042 | doi = 10.1160/th07-03-0199 | s2cid = 17274778 }}</ref> The [https://proteopedia.org/wiki/index.php/SARS-CoV-2_enzyme_Papain-like SARS-CoV-2 papain-like protease (PLpro)] was shown to cleave a sequence (LRGG*KIEVQL) in PROS1.<ref name="reynolds">{{cite journal | vauthors = Reynolds ND, Aceves NM, Liu JL, Compton JR, Leary DH, Freitas BT, Pegan SD, Doctor KZ, Wu FY, Hu X, Legler PM | title = The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease | journal = ACS Infectious Diseases | volume = 7 | issue = 6 | pages = 1483–1502 | date = June 2021 | pmid = 34019767 | pmc = 8171221 | doi = 10.1021/acsinfecdis.0c00866 }}</ref> The cleavage of PROS1 may lead to a transient deficiency in PROS1 during or after infection and may be associated with COVID coagulopathy.<ref name="Baroni, et al">{{cite journal | vauthors = Baroni M, Beltrami S, Schiuma G, Ferraresi P, Rizzo S, Passaro A, Molina JM, Rizzo R, Di Luca D, Bortolotti D | title = In Situ Endothelial SARS-CoV-2 Presence and PROS1 Plasma Levels Alteration in SARS-CoV-2-Associated Coagulopathies | journal = Life | volume = 14 | issue = 2 | page = 237 | date = February 2024 | pmid = 38398746 | pmc = 10890393 | doi = 10.3390/life14020237 | doi-access = free | bibcode = 2024Life...14..237B }}</ref>

== Interactions ==

Protein S has been shown to interact with Factor V.<ref name=pmid10593904>{{cite journal | vauthors = Heeb MJ, Kojima Y, Rosing J, Tans G, Griffin JH | title = C-terminal residues 621-635 of protein S are essential for binding to factor Va | journal = The Journal of Biological Chemistry | volume = 274 | issue = 51 | pages = 36187–36192 | date = December 1999 | pmid = 10593904 | doi = 10.1074/jbc.274.51.36187 | s2cid = 45995946 | doi-access = free }}</ref><ref name=pmid8428962>{{cite journal | vauthors = Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH | title = Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C | journal = The Journal of Biological Chemistry | volume = 268 | issue = 4 | pages = 2872–2877 | date = February 1993 | pmid = 8428962 | doi = 10.1016/S0021-9258(18)53854-0 | doi-access = free }}</ref> A sequence in PROS1 can be cut by the papain-like protease of SARS-CoV-2.<ref name="reynolds" />

==See also== * Hemostasis

==References== {{Reflist|2}}

==Further reading== {{refbegin | 2}} * {{cite journal | vauthors = Dahlbäck B | title = Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system | journal = Thrombosis and Haemostasis | volume = 66 | issue = 1 | pages = 49–61 | date = July 1991 | pmid = 1833851 | doi = 10.1055/s-0038-1646373 | s2cid = 24929072 }} * {{cite journal | vauthors = Witt I | title = [Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein c and protein S] | language = de | journal = Hamostaseologie | volume = 22 | issue = 2 | pages = 14–24 | date = May 2002 | pmid = 12193972 | doi = 10.1055/s-0037-1619540 | trans-title = Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein c and protein S | s2cid = 58077740 }} * {{cite journal | vauthors = Rezende SM, Simmonds RE, Lane DA | title = Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex | journal = Blood | volume = 103 | issue = 4 | pages = 1192–1201 | date = February 2004 | pmid = 12907438 | doi = 10.1182/blood-2003-05-1551 | s2cid = 133028 | doi-access = free }} * {{cite journal | vauthors = Dahlbäck B | title = The tale of protein S and C4b-binding protein, a story of affection | journal = Thrombosis and Haemostasis | volume = 98 | issue = 1 | pages = 90–96 | date = July 2007 | pmid = 17597997 | doi = 10.1160/th07-04-0269 | s2cid = 18823655 }} * {{cite journal | vauthors = García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N | title = Molecular basis of protein S deficiency | journal = Thrombosis and Haemostasis | volume = 98 | issue = 3 | pages = 543–556 | date = September 2007 | pmid = 17849042 | doi = 10.1160/th07-03-0199 | s2cid = 17274778 }} * {{cite journal | vauthors = Maillard C, Berruyer M, Serre CM, Dechavanne M, Delmas PD | title = Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts | journal = Endocrinology | volume = 130 | issue = 3 | pages = 1599–1604 | date = March 1992 | pmid = 1531628 | doi = 10.1210/endo.130.3.1531628 }} * {{cite journal | vauthors = Griffin JH, Gruber A, Fernández JA | title = Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin | journal = Blood | volume = 79 | issue = 12 | pages = 3203–3211 | date = June 1992 | pmid = 1534488 | doi = 10.1182/blood.V79.12.3203.bloodjournal79123203 | doi-access = free }} * {{cite journal | vauthors = Guglielmone HA, Vides MA | title = A novel functional assay of protein C in human plasma and its comparison with amidolytic and anticoagulant assays | journal = Thrombosis and Haemostasis | volume = 67 | issue = 1 | pages = 46–49 | date = January 1992 | pmid = 1615482 | doi = 10.1055/s-0038-1648377 | s2cid = 27769717 }} * {{cite journal | vauthors = Bertina RM, Ploos van Amstel HK, van Wijngaarden A, Coenen J, Leemhuis MP, Deutz-Terlouw PP, van der Linden IK, Reitsma PH | title = Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460 | journal = Blood | volume = 76 | issue = 3 | pages = 538–548 | date = August 1990 | pmid = 2143091 | doi = 10.1182/blood.V76.3.538.538 | doi-access = free }} * {{cite journal | vauthors = Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL | title = Organization of the human protein S genes | journal = Biochemistry | volume = 29 | issue = 34 | pages = 7845–7852 | date = August 1990 | pmid = 2148110 | doi = 10.1021/bi00486a010 }} * {{cite journal | vauthors = Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM | title = Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution | journal = Biochemistry | volume = 29 | issue = 34 | pages = 7853–7861 | date = August 1990 | pmid = 2148111 | doi = 10.1021/bi00486a011 }} * {{cite journal | vauthors = Allaart CF, Aronson DC, Ruys T, Rosendaal FR, van Bockel JH, Bertina RM, Briët E | title = Hereditary protein S deficiency in young adults with arterial occlusive disease | journal = Thrombosis and Haemostasis | volume = 64 | issue = 2 | pages = 206–210 | date = October 1990 | doi = 10.1055/s-0038-1647286 | pmid = 2148653 }} * {{cite journal | vauthors = Ohlin AK, Landes G, Bourdon P, Oppenheimer C, Wydro R, Stenflo J | title = Beta-hydroxyaspartic acid in the first epidermal growth factor-like domain of protein C. Its role in Ca2+ binding and biological activity | journal = The Journal of Biological Chemistry | volume = 263 | issue = 35 | pages = 19240–19248 | date = December 1988 | pmid = 2461936 | doi = 10.1016/S0021-9258(18)37415-5 | doi-access = free }} * {{cite journal | vauthors = Schwarz HP, Heeb MJ, Lottenberg R, Roberts H, Griffin JH | title = Familial protein S deficiency with a variant protein S molecule in plasma and platelets | journal = Blood | volume = 74 | issue = 1 | pages = 213–221 | date = July 1989 | pmid = 2526663 | doi = 10.1182/blood.V74.1.213.213 | doi-access = free }} * {{cite journal | vauthors = Ploos van Amstel HK, van der Zanden AL, Reitsma PH, Bertina RM | title = Human protein S cDNA encodes Phe-16 and Tyr 222 in consensus sequences for the post-translational processing | journal = FEBS Letters | volume = 222 | issue = 1 | pages = 186–190 | date = September 1987 | pmid = 2820795 | doi = 10.1016/0014-5793(87)80217-X | s2cid = 46365357 | doi-access = free | bibcode = 1987FEBSL.222..186V }} * {{cite journal | vauthors = Dahlbäck B, Lundwall A, Stenflo J | title = Primary structure of bovine vitamin K-dependent protein S | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 12 | pages = 4199–4203 | date = June 1986 | pmid = 2940598 | pmc = 323699 | doi = 10.1073/pnas.83.12.4199 | doi-access = free | bibcode = 1986PNAS...83.4199D }} * {{cite journal | vauthors = Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlbäck B, Stenflo J, Wydro R | title = Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 18 | pages = 6716–6720 | date = September 1986 | pmid = 2944113 | pmc = 386580 | doi = 10.1073/pnas.83.18.6716 | doi-access = free | bibcode = 1986PNAS...83.6716L }} * {{cite journal | vauthors = Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM | title = Hereditary protein S deficiency: clinical manifestations | journal = Annals of Internal Medicine | volume = 106 | issue = 5 | pages = 677–682 | date = May 1987 | pmid = 2952034 | doi = 10.7326/0003-4819-106-5-677 }} * {{cite journal | vauthors = Watkins PC, Eddy R, Fukushima Y, Byers MG, Cohen EH, Dackowski WR, Wydro RM, Shows TB | title = The gene for protein S maps near the centromere of human chromosome 3 | journal = Blood | volume = 71 | issue = 1 | pages = 238–241 | date = January 1988 | pmid = 2961379 | doi = 10.1182/blood.V71.1.238.238 }} {{refend}}

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Category:Coagulation system