Protein S

Last updated

PROS1
Protein PROS1 PDB 1z6c.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PROS1 , PROS, PS21, PS22, PS23, PS24, PS25, PSA, THPH5, THPH6, protein S (alpha), protein S
External IDs OMIM: 176880; MGI: 1095733; HomoloGene: 264; GeneCards: PROS1; OMA:PROS1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5627

19128

Ensembl

ENSG00000184500

ENSMUSG00000022912

UniProt

P07225

Q08761

RefSeq (mRNA)

NM_000313
NM_001314077

NM_011173

RefSeq (protein)

NP_000304
NP_001301006

NP_035303

Location (UCSC) Chr 3: 93.87 – 93.98 Mb Chr 16: 62.67 – 62.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] Protein S plays a role in coagulation.

Contents

History

Protein S is named for Seattle, Washington, where it was originally discovered and purified [7] by Earl Davie's group in 1977. [8]

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. [9] [10]

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. [11]

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. [12]

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. [13] [14]

Interactions

Protein S has been shown to interact with Factor V. [15] [16]

See also

Related Research Articles

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Factor VIII</span> Blood-clotting protein

Coagulation factor VIII is an essential blood clotting protein. In humans, it is encoded by F8 gene. Defects in this gene result in hemophilia A, an X-linked bleeding disorder.

<span class="mw-page-title-main">Protein S deficiency</span> Medical condition

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor VIIIa.

<span class="mw-page-title-main">Protein C</span> Mammalian protein found in Homo sapiens

Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease since it contains a residue of serine in its active site. In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.

<span class="mw-page-title-main">Factor V</span> Mammalian protein found in humans

Coagulation factor V, also less commonly known as proaccelerin or labile factor, is a protein involved in coagulation, encoded, in humans, by F5 gene. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Factor V deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (factor II), an inactive zymogen, to thrombin (factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

<span class="mw-page-title-main">Protein C deficiency</span> Medical condition

Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found.

<span class="mw-page-title-main">Phospholipid scramblase</span> Protein

Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases, flippases, and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet, facing the inside of the cell, contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme, present in the cell membrane, that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet, and vice versa.

<span class="mw-page-title-main">Heparin cofactor II</span> Protein-coding gene in the species Homo sapiens

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.

<span class="mw-page-title-main">Protein C inhibitor</span> Human protein

Protein C inhibitor is a serine protease inhibitor (serpin) that limits the activity of protein C.

<span class="mw-page-title-main">Gamma-glutamyl carboxylase</span>

Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12.

<span class="mw-page-title-main">Apolipoprotein H</span> Protein-coding gene in humans

β2-glycoprotein 1, also known as beta-2 glycoprotein 1 and Apolipoprotein H (Apo-H), is a 38 kDa multifunctional plasma protein that in humans is encoded by the APOH gene. One of its functions is to bind cardiolipin. When bound, the structure of cardiolipin and β2-GP1 both undergo large changes in structure. Within the structure of Apo-H is a stretch of positively charged amino acids, Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding.

<span class="mw-page-title-main">Gla domain</span>

Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins with this domain are known informally as Gla proteins. The Gla residues are responsible for the high-affinity binding of calcium ions.

<span class="mw-page-title-main">Coagulation factor XIII A chain</span> Protein found in humans

Coagulation factor XIII A chain, (FXIIIa) is a protein that in humans is encoded by the F13A1 gene.

<span class="mw-page-title-main">Coagulation factor XIII B chain</span> Mammalian protein found in Homo sapiens

Coagulation factor XIII B chain is a protein that in humans is encoded by the F13B gene.

<span class="mw-page-title-main">Carboxypeptidase B2</span>

Carboxypeptidase B2 (CPB2), also known as carboxypeptidase U (CPU), plasma carboxypeptidase B (pCPB) or thrombin-activatable fibrinolysis inhibitor (TAFI), is an enzyme that, in humans, is encoded by the gene CPB2.

<span class="mw-page-title-main">Endothelial protein C receptor</span> Protein-coding gene in the species Homo sapiens

Endothelial protein C receptor (EPCR) also known as activated protein C receptor is a protein that in humans is encoded by the PROCR gene. PROCR has also recently been designated CD201.

<span class="mw-page-title-main">Multimerin 1</span> Protein-coding gene in the species Homo sapiens

Multimerin 1, also known as elastin microfibril interfacer 4 (EMILIN-4), is a protein that, in humans, is encoded by the MMRN1 gene.

<span class="mw-page-title-main">Scott syndrome</span> Medical condition

Scott syndrome is a rare congenital bleeding disorder that is due to a defect in a platelet mechanism required for blood coagulation.

Björn Dahlbäck is a Swedish physician, medical researcher, and professor of clinical chemistry, specializing in hematology and the molecular mechanisms of blood coagulation. He determined that activated protein C (APC) resistance is the most common inherited risk factor of venous thrombosis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000184500 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022912 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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. Bibcode:1986PNAS...83.6716L. doi: 10.1073/pnas.83.18.6716 . PMC   386580 . PMID   2944113.
  6. ↑ 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. PMID   2829367. S2CID   31236887.
  7. ↑ "Protein S deficiency". UpToDate. Retrieved May 10, 2017.
  8. ↑ Kaushansky K, Lichtman M, Prchal J, Levi M, Press O, Burns L, Caligiuri M (2015). Williams Hematology. McGraw-Hill. p. 1926.
  9. ↑ Stenflo J (1999). "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. doi:10.1615/CritRevEukaryotGeneExpr.v9.i1.50. PMID   10200912.
  10. ↑ Rosner W (Dec 1991). "Plasma steroid-binding proteins". Endocrinology and Metabolism Clinics of North America. 20 (4): 697–720. doi:10.1016/S0889-8529(18)30240-8. PMID   1778174.
  11. ↑ Dahlbäck B, Lundwall A, Stenflo J (Jun 1986). "Primary structure of bovine vitamin K-dependent protein S". Proceedings of the National Academy of Sciences. 83 (12): 4199–203. Bibcode:1986PNAS...83.4199D. doi: 10.1073/pnas.83.12.4199 . PMC   323699 . PMID   2940598.
  12. ↑ 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. S2CID   11522770.
  13. ↑ 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. S2CID   705661.
  14. ↑ 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. doi:10.1160/th07-03-0199. PMID   17849042. S2CID   17274778.
  15. ↑ Heeb MJ, 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). UNITED STATES: 36187–92. doi: 10.1074/jbc.274.51.36187 . ISSN   0021-9258. PMID   10593904. S2CID   45995946.
  16. ↑ Heeb MJ, 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). UNITED STATES: 2872–7. doi: 10.1016/S0021-9258(18)53854-0 . ISSN   0021-9258. PMID   8428962.

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