Protein S

History

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

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.

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.

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.

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. The SARS-CoV-2 papain-like protease (PLpro) was shown to cleave a sequence (LRGG*KIEVQL) in PROS1. The cleavage of PROS1 may lead to a transient deficiency in PROS1 during or after infection and may be associated with COVID coagulopathy.

Interactions

Protein S has been shown to interact with Factor V. A sequence in PROS1 can be cut by the papain-like protease of SARS-CoV-2.

References

References

1. (September 1986). "Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation". Proceedings of the National Academy of Sciences of the United States of America.
2. (January 1988). "Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively". Somatic Cell and Molecular Genetics.
3. (February 2025). "Protein S deficiency".
4. (2015). "Williams Hematology". McGraw-Hill.
5. (1999). "Contributions of Gla and EGF-like domains to the function of vitamin K-dependent coagulation factors". Critical Reviews in Eukaryotic Gene Expression.
6. (December 1991). "Plasma steroid-binding proteins". Endocrinology and Metabolism Clinics of North America.
7. (June 1986). "Primary structure of bovine vitamin K-dependent protein S". Proceedings of the National Academy of Sciences of the United States of America.
8. (September 2008). "Regulation of coagulation by protein S". Current Opinion in Hematology.
9. (June 2004). "The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population". British Journal of Haematology.
10. (September 2007). "Molecular basis of protein S deficiency". Thrombosis and Haemostasis.
11. (June 2021). "The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease". ACS Infectious Diseases.
12. (February 2024). "In Situ Endothelial SARS-CoV-2 Presence and PROS1 Plasma Levels Alteration in SARS-CoV-2-Associated Coagulopathies". Life.
13. (December 1999). "C-terminal residues 621-635 of protein S are essential for binding to factor Va". The Journal of Biological Chemistry.
14. (February 1993). "Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C". The Journal of Biological Chemistry.