Protein S (also known as PROS) is a
vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
-dependent plasma
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
synthesized in the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
. In the circulation, Protein S exists in two forms: a free form and a complex form bound to
complement
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-class ...
protein
C4b-binding protein
C4b-binding protein (C4BP) is a protein complex involved in the complement system where it acts as inhibitor. C4BP has an octopus-like structure with a central stalk and seven branching alpha-chains. The main form of C4BP in human blood is compos ...
(C4BP). In humans, protein S is encoded by the ''PROS1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Protein S plays a role in coagulation.
History
Protein S is named for Seattle, Washington, where it was originally discovered and purified by
Earl Davie
Earl Warren Davie (October 25, 1927 - June 6, 2020) was an American biochemist. He was a professor emeritus of biochemistry at the University of Washington. Davie studied the blood proteins involved in coagulation and was among the first scientist ...
's group in 1977.
Structure
Protein S is partly
homologous to other vitamin K-dependent plasma coagulation proteins, such as
protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and apoptosis, cell death and ...
and factors
VII VII or vii may refer to: the Roman numeral 7
Art and entertainment
* The Vii, a video game console
* vii, leading-tone triad, see diminished triad
* ''VII'' (Blitzen Trapper album)
* ''VII'' (Just-Ice album)
* ''VII'' (Teyana Taylor album)
* ...
,
IX, and
X. Similar to them, it has a
Gla domain
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 wit ...
and several
EGF-like domain
The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostl ...
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
Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen-bi ...
and
corticosteroid-binding globulin
Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein produced in the liver in animals. In humans it is encoded by the SERPINA6 gene. It is an alpha-globulin.
Function
This gene encodes an alpha-globulin pro ...
. It may play a role in the protein functions as either a
cofactor for
activated protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining ...
(APC) or in binding
C4BP
C4b-binding protein (C4BP) is a protein complex involved in the complement system where it acts as inhibitor. C4BP has an octopus-like structure with a central stalk and seven branching alpha-chains. The main form of C4BP in human blood is compos ...
.
Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by
thrombin
Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
. The Gla and EGF-like domains stay connected after the cleavage by a
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
. 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
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
pathway, where it functions as a cofactor to
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and apoptosis, cell death and ...
in the inactivation of
Factors Va and
VIIIa. Only the free form has cofactor activity.
Protein S binds to negatively charged
phospholipids
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
via the carboxylated Gla domain. This property allows Protein S to facilitate the removal of cells that are undergoing
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, a form of structured cell death used by the body to remove unwanted or damaged cells. In healthy cells, an ATP (
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
)-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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
) 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
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek '' ...
such as
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
. 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
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
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
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 V ...
which is a rare blood disorder which can lead to an increased risk of
thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
.
Interactions
Protein S has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
Factor V
Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficienc ...
.
See also
*
Hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
References
Further reading
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{{Glycoproteins
Coagulation system