PROCR - protein C receptor |Elisa - Clia - Antibody - Protein

Background

PROCR, also known as the endothelial protein C receptor (EPCR), is a critical component of the protein C anticoagulant pathway. This pathway has essential roles in regulating blood coagulation, inflammation, and maintaining vascular integrity. PROCR is primarily expressed on endothelial cells lining blood vessels and binds to activated protein C (APC) to enhance its anticoagulant effects. This interaction is vital for limiting thrombosis, mitigating inflammation, and preserving the barrier function of blood vessels, especially in response to inflammatory and coagulatory challenges. Recent research has revealed additional roles for PROCR, including functions in immune response modulation, cell proliferation, and tissue regeneration.

Protein Structure

The structure of PROCR is typical of a type I transmembrane protein, with distinct domains that are critical for its functions:

Extracellular Domain:

• PROCR’s extracellular domain contains an immunoglobulin-like fold, similar to members of the immunoglobulin superfamily. This domain is responsible for the high-affinity binding to protein C and APC.
• The specific binding region of PROCR to protein C resides within amino acid residues that form a unique structure capable of recognizing and binding the γ-carboxyglutamic acid-rich (Gla) domain of protein C. This interaction is calcium-dependent and leads to the activation of protein C on the surface of endothelial cells.

Transmembrane Domain:

• PROCR contains a single-pass transmembrane region that anchors it to the endothelial cell membrane. This domain is composed of hydrophobic amino acids, contributing to the structural stability of PROCR within the cell membrane.

Cytoplasmic Tail:

• The cytoplasmic tail of PROCR is relatively short and lacks enzymatic activity, indicating that the receptor does not engage directly in signal transduction. However, its location at the cell surface facilitates the binding and activation of protein C, leading to subsequent downstream signaling pathways.

Soluble Form:

• In addition to the membrane-bound form, PROCR can be cleaved by metalloproteinases, releasing a soluble form of the receptor (sEPCR) into the plasma. sEPCR retains the ability to bind to protein C and APC, though its biological effects differ from those of the membrane-bound form.

Classification and Subtypes

PROCR is classified as a type I transmembrane protein and belongs to the immunoglobulin superfamily due to its extracellular immunoglobulin-like fold. It is encoded by the PROCR gene on chromosome 20 (20q11.2) in humans. Although there are no true subtypes of PROCR, two functional forms exist:

• Membrane-bound PROCR: Primarily responsible for promoting APC’s anticoagulant and anti-inflammatory functions.
• Soluble PROCR (sEPCR): Produced through cleavage of the membrane-bound form, has distinct effects on coagulation and inflammation. The role of sEPCR in disease processes is complex, as it can either neutralize or inhibit the effects of APC.

Function and Biological Significance

The primary role of PROCR is to mediate the activation of protein C, which is a critical process in the regulation of blood coagulation, inflammation, and cell survival. By binding to APC, PROCR enhances its ability to inactivate clotting factors Va and VIIIa, thereby reducing thrombin formation. Beyond hemostasis, PROCR has significant functions in maintaining vascular integrity and immune response modulation.

Anticoagulant Function:

• The binding of protein C to PROCR promotes its activation by thrombin-thrombomodulin complexes. Once activated, APC degrades coagulation factors Va and VIIIa, reducing thrombin formation and preventing the formation of blood clots. This anticoagulant activity is particularly important in preventing thrombotic events in response to endothelial injury.

Anti-inflammatory Effects:

• APC binding to PROCR activates protective intracellular pathways, particularly through protease-activated receptor 1 (PAR-1). This signaling pathway suppresses the release of pro-inflammatory cytokines and inhibits leukocyte adhesion to the endothelium, thus reducing inflammation in response to injury or infection.

Endothelial Barrier Function:

• APC signaling through PROCR enhances endothelial cell survival and maintains vascular barrier function, which is essential in conditions where vascular integrity is compromised, such as sepsis or ischemia-reperfusion injury. This function also aids in limiting excessive inflammatory responses.

Immune Modulation:

• Recent studies indicate that PROCR and APC interactions play a role in modulating immune responses by affecting cytokine production and leukocyte behavior. This function suggests PROCR’s involvement in immune tolerance and potentially in autoimmune disease modulation.

Cellular Proliferation and Tissue Regeneration:

• Beyond its established roles, PROCR has been implicated in supporting tissue repair and regeneration. Through APC-mediated signaling, PROCR may promote cell proliferation and survival, suggesting a potential role in wound healing and tissue homeostasis.

Clinical Issues

Dysregulation of PROCR expression or function has been associated with various clinical conditions, including thrombosis, inflammation, sepsis, and cancer.

Thrombotic Disorders:

• Mutations or polymorphisms in the PROCR gene that affect its function or expression can lead to an increased risk of venous thromboembolism and other thrombotic conditions. Reduced expression or loss-of-function mutations impair the protein C anticoagulant pathway, predisposing individuals to clot formation.
• Elevated levels of sEPCR are also associated with an increased risk of thrombosis, as sEPCR can inhibit the anticoagulant action of APC by competing for protein C binding.

Inflammatory Conditions and Sepsis:

• PROCR is involved in the regulation of inflammatory responses, particularly during sepsis. High levels of sEPCR are often observed in sepsis patients, which correlates with disease severity. Increased sEPCR can bind to APC, neutralizing its anti-inflammatory effects and contributing to the inflammatory cascade in septic shock.
• The protective role of membrane-bound PROCR in reducing endothelial permeability and inflammation is crucial in sepsis, where vascular leakage and inflammation are prominent.

Cancer:

• PROCR expression has been linked to tumor progression and metastasis in certain cancers, such as colorectal and breast cancers. APC-PROCR signaling may facilitate tumor cell survival, migration, and immune evasion, which supports cancer growth and metastasis.
• Elevated sEPCR levels have also been observed in cancer patients, though the functional significance of sEPCR in cancer remains an area of active research.

Autoimmune Diseases:

• Due to its immune-modulatory effects, PROCR is thought to play a role in autoimmune diseases. Altered expression of PROCR or dysfunction in its signaling pathway could contribute to immune dysregulation seen in diseases like multiple sclerosis and rheumatoid arthritis.

Summary

PROCR, or endothelial protein C receptor, is a type I transmembrane protein with a critical role in the protein C anticoagulant pathway, which regulates blood coagulation, inflammation, and vascular barrier integrity. Structurally, PROCR features an extracellular domain that binds to protein C, a transmembrane domain that anchors it to the cell membrane, and a short cytoplasmic tail. In addition to its membrane-bound form, a soluble form of PROCR (sEPCR) is produced through cleavage, with distinct functional implications.

The biological significance of PROCR is vast, as it modulates coagulation, reduces inflammation, and protects vascular endothelial cells, making it an essential molecule in maintaining vascular homeostasis. Dysfunction of PROCR due to genetic mutations, altered expression, or elevated sEPCR levels is associated with thrombotic disorders, sepsis, cancer, and inflammatory diseases. Given its crucial role in various physiological and pathological processes, PROCR remains a significant target for therapeutic intervention in diseases involving coagulation, inflammation, and immune modulation.