# Protein S
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{{Short description|Vitamin K-dependent plasma glycoprotein synthesized in the liver}}
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'''Protein S''' (also known as '''PROS''') is a [vitamin K](/source/vitamin_K)-dependent plasma [glycoprotein](/source/glycoprotein) synthesized in the [liver](/source/liver). In the circulation, Protein S exists in two forms: a free form and a complex form bound to [complement](/source/complement_system) protein [C4b-binding protein](/source/C4b-binding_protein) (C4BP). In humans, protein S is encoded by the ''PROS1'' [gene](/source/gene).[{{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 = 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 }}] Protein S plays a role in coagulation.
==History==
Protein S is named for Seattle, Washington, where it was originally discovered and purified[{{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§ionRank=1&anchor=H3#H3|website=UpToDate|access-date=May 10, 2017}}] by [Earl Davie](/source/Earl_Davie)'s group in 1977.[{{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}}]
== Structure ==
Protein S is partly [homologous](/source/homology_(biology)) to other vitamin K-dependent plasma coagulation proteins, such as [protein C](/source/protein_C) and factors [VII](/source/factor_VII), [IX](/source/factor_IX), and [X](/source/factor_X). Similar to them, it has a [Gla domain](/source/Gla_domain) and several [EGF-like domain](/source/EGF-like_domain)s (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](/source/sex_hormone-binding_globulin) and [corticosteroid-binding globulin](/source/corticosteroid-binding_globulin). It may play a role in the protein functions as either a [cofactor](/source/cofactor_(biochemistry)) for [activated protein C](/source/activated_protein_C) (APC) or in binding [C4BP](/source/C4BP).[{{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 }}][{{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 }}]
Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by [thrombin](/source/thrombin). The Gla and EGF-like domains stay connected after the cleavage by a [disulfide bond](/source/disulfide_bond). However, protein S loses its function as an APC cofactor following either this cleavage or binding C4BP.[{{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 }}]
== Function ==
The best characterized function of Protein S is its role in the anti [coagulation](/source/coagulation) pathway, where it functions as a cofactor to [Protein C](/source/Protein_C) in the inactivation of [Factors Va](/source/factor_V) and [VIIIa](/source/factor_VIII). Only the free form has cofactor activity.[{{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 }}]
Protein S binds to negatively charged [phospholipids](/source/phospholipids) via the carboxylated Gla domain. This property allows Protein S to facilitate the removal of cells that are undergoing [apoptosis](/source/apoptosis), a form of structured cell death used by the body to remove unwanted or damaged cells. In healthy cells, an ATP ([adenosine triphosphate](/source/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](/source/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](/source/phagocytes) such as [macrophages](/source/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](/source/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](/source/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](/source/Protein_S_deficiency) which is a rare blood disorder which can lead to an increased risk of [thrombosis](/source/thrombosis).[{{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 }}][{{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 }}] 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.[{{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 }}] The cleavage of PROS1 may lead to a transient deficiency in PROS1 during or after infection and may be associated with [COVID coagulopathy](/source/Symptoms_of_COVID-19).[{{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 }}]
== Interactions ==
Protein S has been shown to [interact](/source/protein%E2%80%93protein_interaction) with [Factor V](/source/Factor_V).[{{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 }}][{{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 }}] A sequence in PROS1 can be cut by the papain-like protease of SARS-CoV-2.