Proteins are the building blocks of cells and facilitate various critical functions. One of these proteins, known as Human Protein C (PC), carries immense clinical relevance due to its role in maintaining blood homeostasis.
Background Information of Human Protein C
Around 50 years ago, Human Protein C was first discovered in plasma during the exploration of coagulation mechanisms. Found to play a crucial part in regulating blood clotting, this vitamin K-dependent protein is synthesized in the liver. The PC gene that encodes for Human Protein C is located on chromosome 2 at locus 2q13–14. This gene spans over 11 kilobases and comprises nine exons and eight introns. The Vitamin K-dependent Protein C is initially synthesized as a precursor containing 461 amino acids, which are later processed to form mature Protein C.
The protein structure incorporates a light and a heavy chain. The light chain harbors the Gla domain, which chelates calcium ions and assists in membrane binding. Consequently, the heavy chain possesses the serine protease domain critical to its enzymatic activities. Together, these structural attributes of Protein C underscore its valuable roles in various biological functions.
Function of Human Protein C
In its inactive state, Human Protein C circulates in the bloodstream. However, upon activation by the thrombin-thrombomodulin complex, it turns into an active enzyme known as activated Protein C (aPC). aPC is endowed with several crucial roles, including regulating blood clotting, exhibiting anti-inflammatory, cytoprotective, and neuroprotective properties.
Mainly, aPC works as an anticoagulant by inhibiting factors Va and VIIIa, reducing thrombin generation and clot formation. Therefore, the primary function of Human Protein C is to halt excessive coagulation, ensuring the fluidity of blood and offsetting the risk of developing blood clots that could potentially lead to life-threatening conditions such as stroke or pulmonary embolism.
Human Protein C-related Signaling Pathways
Human Protein C orchestrates with several signaling pathways to realize its vast repertoire of functions. A key signaling pathway that involves aPC is the protease activated receptor 1 (PAR1) pathway, a pivotal link between coagulation and inflammation. aPC facilitates cytoprotective signaling by modifying the PAR1 signaling pathway.
Human Protein C also interacts with the EPCR (Endothelial Protein C Receptor), which aids in presenting Protein C to the thrombin-thrombomodulin complex, enhancing its activation. After activation, aPC-EPCR complex alters the downstream signaling pathway, reducing inflammation and ensuring endothelial barrier protection.
Human Protein C Related Diseases and its Role in Disease
Human Protein C deficiency, caused by mutations in the Protein C gene, can lead to several diseases. Individuals deficient in Protein C are prone to developing venous thromboembolism due to unchecked clotting. An inherited risk factor for venous thrombosis, Protein C deficiency could cause a severe neonatal purpura fulminans, a disease characterized by extensive clotting leading to skin necrosis and life-threatening systemic complications.
Severe sepsis and systemic inflammation are other conditions where Human Protein C's function becomes crucial. During such conditions, the Protein C pathway is downregulated, leading to coagulation abnormalities and enhanced inflammation.
Application of Human Protein C
Given its crucial role in maintaining haemostasis and providing cytoprotection, Human Protein C has several therapeutic applications. Activated Protein C was once used as a treatment for severe sepsis under the brand name Xigris, but it was withdrawn in 2011 due to insufficient proof of its risk/benefit ratio. Newer studies propose that selectively cytoprotective, non-anticoagulant variants of activated Protein C may have potential therapeutic prospects in several diseases, including sepsis, stroke, multiple sclerosis, and neurodegenerative diseases.
Given the remarkable and multi-faceted roles played by Human Protein C, it continues to be a subject of exhaustive study and intense scrutiny. With a better understanding of its functions and the signaling pathways, it can manipulate, devise better therapeutic strategies to manage a spectrum of diseases where Protein C plays a key role. Its nuanced functionalities, beyond the realms of coagulation, offer promising new avenues for further research and clinical applications.