DEFINITION
Protein S (PS) is K-dependent plasma glycoprotein.
PROS1 gene is located near centromere on chromosome 3q11.2 and it contains 15 exons.
Protein S has an important function in the down-regulation of thrombin generation.
PS is particularly difficult to study because of the existence of a pseudogene and two different protein forms (a bound and a free form) circulating in plasma. Around 60-70% of PS in plasma is bound to a carrier protein, known as C4BP. The free form acts as an enhancer for the activity of the activated protein C (APC) in proteolytic degradation of factors V and VIII.
Recently has been discovered protein S APC-indipendent activity to directly inhibit prothrombinase. PS seems to directly bind factors V, VIII and X.
Wikipedia
Protein S defiency: a clinical perspective, 2008
CHEMICAL STRUCTURE AND IMAGES
Protein S is a 635 aminoacids glycoprotein, with molecular mass of 69 kDa.
PS is composed of an N-terminal Gla (gamma-carboxyglutamic acid) domain which is a thrombine-sensitive region and allows PS to directly bind activated coagulation factors, 4 consecutive epidermal growth factor-like domains and on C-terminal a sex hormone-binding-like domain (SHBG).
SYNTHESIS AND TURNOVER
mRNA synthesis
The PROS1 gene spans about 101 kb of DNA containing 15 exons and it's transcribed into a 3,3 kb of mRNA. More than 200 mutations of PROS1 have been reported.
Post transcriptional modifications
mRNA transcription can be down-regulated by microRNA (miR-494).
Protein S is mainly synthesized and secreted by hepatocytes. PS secreted by liver has and anticoagulant activity , contrary to PS secreted by other cell types like megakaryocytes, endothelial cells, Leydig and Sertoli cells, osteoblasts, dendritic cells, T cells and vascular smooth muscle cells.
Those cells secrete Protein S without any anticoagulant activity, but rather function to activate a family of protein-tyrosine receptors (PTK).
Degradation
The biological Protein S half-life in plasma is about 30-42 hours.
Enzyme
BIOLOGICAL FUNCTION :
ANTICOAGULANT ACTIVITY
Protein S is able to bind negative charged phospholipids of cellular membrane and helps to localize APC to the membrane surface. In doing so, APC is localized in proximity to factors V and VIII.
Protein S enhances Protein C activity by positioning in the active site of APC, which acquires the ability to cleave factors V and VIII.
Protein S molecular mechanism is not completely known yet, but there are many evidences that PS reduced activity is due to a switch of the Asp95 to Asn rather than Ala.
The role of Asp95 is critic in APC recognition, forming the main interaction site for Protein C.
Activated Protein C cofactors function of Protein S: a critical role of Asp95 in the EGF-like domain, 2010
ROLE OF PROTEIN S IN INFLAMMATION
Protein S is able to bind PTK receptors.
PTK receptors are members of the TAM receptors family and they are involved in several physiological processes, such as cell proliferation/survival, apoptosis, regulation of inflammatory cytokines release, atherosclerosis, vasculogenesis and cancer development.
Protein S has been also identified as the factor that mediates the macrophage phagocytosis of apoptotic cells, exclusively binding phosphatidil-serine-positive apoptotic bodies with a calcium dependent mechanism.
TAM receptors are thought to be significant in the regulation of inflammatory processes acting both in TRL signalling pathways and in the release of cytokines. Protein S is able to bind a subtype of TAM receptors, inhibiting the expression of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1), and to inhibit TRL activation.
Protein S appears to be an important actor of the anti-inflammatory macrophage cell response contributing to the activation of TAM receptors response.
Protein S: a multifunctional anticoagulant K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis and cancer, 2013
HORMONAL REGULATION
Protein S levels are strongly influenced by hormonal state, liver disease and disseminated intravascular coagulation.
Estrogens can modulate the expression of the PROS1 gene in multiple tissues and organs, inducing the MAPK cascade by binding the ER intracellular receptor. The estrogens signalling performs a repression of PROS1 translation, providing the synthesis of microRNA (miR-494) which causes the degradation of the PROS1 mRNA.
This finding agrees with many studies that showed how sex-hormones therapies, like estrogenic contraceptives, increase the risk of venous thromboembolic disease.
The risk to develop a deep vein thrombosis and a subsequent pulmonary embolism can be reduced with progestin contraceptives. Studies shows that progesterone increase the transcription of PROS1
by 25%.
Protein S: a multifunctional anticoagulant K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis and cancer, 2013
DIAGNOSIS
The diagnosis of PS deficiency is challenging.
There are several factors which can affect PS levels, usually related with protein c levels. Molecular analysis are requested in order to find a mutation on PROS1 and they involves direct gene sequencing or, if negative, multiplex ligation-dependent probe amplification method.
Protein C and Protein S deficiency – practical diagnostic issues, 2013
MEDICAL IMPORTANCE
Protein s deficiency is a rare condition which can predispose individuals to hypercoagulability.
Deficiency occurs in case of homozygous mutation on gene PROS1 and usually leads to fetal loss or neonatal purpura fulminans.
Neonatal purpura fulminans is rare life-threatening disorder of dermal microvascular thrombosis associated with disseminated intravascular coagulation and perivascular haemorrhage. The fist clinical sign is the haemorrhagic necrosis of the skin. This coagulation disorder could be acquired or inherited, and the main causes are liver failure or protein C and S deficiency.
Adults who carries a heterozygous missense mutation on PROS1 are predisposed to deep vein thrombosis, strokes and pulmonary embolism. The association of PS deficiency to vein thrombosis is proven, although protein s seems not to be connected with arterial thrombosis.
Protein s deficiency could be acquired in vitamin K deficiency, warfarin or sex hormone therapy, pregnancy, liver disease and infections, such as staphylococcal endocarditis.
PS heterozygous deficiency could lead to a bacterial infection. Thrombophilia is probable one of the factors responsible of endocarditis.
Staphylococcal Endocarditis as the first manifestation of Protein S deficiency in childhood 2013
Diagnosis and management of neonatal purpura fulminans, 2011
