SERPINE1 - serpin family E member 1 |Elisa - Clia - Antibody - Protein

Background

SERPINE1, also known as Plasminogen Activator Inhibitor-1 (PAI1), is a serine protease inhibitor that plays a key role in the regulation of fibrinolysis, the process that breaks down blood clots. It belongs to the serpin superfamily, which is a group of proteins involved in the inhibition of proteases. Specifically, SERPINE1 inhibits tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), both of which are enzymes responsible for converting plasminogen into plasmin, a protease that degrades fibrin, the main component of blood clots.

The regulation of PAI-1 levels is crucial for maintaining the balance between clot formation and breakdown in the body. Abnormally high levels of PAI-1 are associated with thrombotic conditions, whereas deficiencies can lead to excessive bleeding. Beyond its role in fibrinolysis, PAI-1 is also implicated in various other biological processes, including tissue remodeling, inflammation, wound healing, and tumor progression.

Protein Structure

SERPINE1 is a 402-amino acid glycoprotein with a molecular weight of approximately 50 kDa. Like other members of the serpin family, it has a conserved serpin fold, consisting of three β-sheets and several α-helices. The characteristic feature of serpins is their reactive center loop (RCL), which serves as a bait for target proteases. When a protease cleaves the RCL, SERPINE1 undergoes a dramatic conformational change, trapping the protease in a covalent complex and inactivating it.

SERPINE1 contains a highly flexible RCL that allows it to interact with tPA and uPA. Once bound, it inhibits these proteases by forming a stable complex, thus preventing the conversion of plasminogen to plasmin. This structure-function relationship is critical to its role in regulating fibrinolysis. PAI-1 also has glycosylation sites that contribute to its stability and functional activity in circulation.

An important structural feature of PAI-1 is its metastability. In its active form, it can spontaneously convert to an inactive, latent form. The conversion from active to latent PAI-1 involves the insertion of the RCL into the body of the serpin fold, making it unavailable for interaction with proteases. This transition between active and inactive states is a crucial regulatory mechanism for controlling PAI-1 activity in physiological conditions.

Classification and Subtypes

SERPINE1 is classified under the "E" family of serpins (serine protease inhibitors) due to its inhibitory role in the fibrinolytic system. It is a single gene product without significant isoforms or subtypes that have been functionally characterized. However, genetic polymorphisms in the SERPINE1 gene can influence the expression and function of PAI-1, potentially affecting its role in clot formation and degradation.

For example, the 4G/5G polymorphism in the promoter region of SERPINE1 affects PAI-1 plasma levels. Individuals with the 4G allele have higher levels of PAI-1, which can predispose them to thrombotic conditions, while those with the 5G allele may have lower levels.

Function and Biological Significance

SERPINE1’s primary function is the inhibition of the plasminogen activators, tPA and uPA. By inhibiting these activators, PAI-1 prevents the conversion of plasminogen into plasmin, thereby regulating the breakdown of fibrin clots. This role in fibrinolysis makes SERPINE1 essential for maintaining the balance between clot formation and breakdown, ensuring proper wound healing and preventing excessive bleeding or thrombosis.

In normal physiological conditions, PAI-1 is expressed in several tissues, including the liver, endothelium, adipose tissue, and platelets. Its expression can be induced by a variety of factors, such as inflammatory cytokines, growth factors, and hormones like insulin and glucocorticoids. PAI-1 levels are also known to fluctuate in response to metabolic conditions like obesity, insulin resistance, and hyperglycemia.

Beyond fibrinolysis, PAI-1 has important roles in other biological processes:

1. Tissue Remodeling: PAI-1 is involved in wound healing and tissue remodeling by regulating extracellular matrix (ECM) turnover. It inhibits proteases that degrade ECM components, thus influencing cell migration and tissue repair.
2. Inflammation: PAI-1 is upregulated in response to inflammatory signals and is involved in modulating immune cell recruitment and activation. Elevated PAI-1 levels are observed in chronic inflammatory conditions, including atherosclerosis and obesity.
3. Tumor Progression: PAI-1 has been implicated in cancer biology, particularly in the processes of tumor invasion and metastasis. It regulates cell adhesion and migration by modulating ECM degradation, which is critical for tumor cells to invade surrounding tissues and metastasize.

Clinical Issues

Thrombosis: Elevated levels of PAI-1 are associated with an increased risk of thrombotic disorders, such as deep vein thrombosis (DVT), myocardial infarction, and stroke. This is because high PAI-1 activity inhibits fibrinolysis, leading to a reduced breakdown of blood clots. Individuals with certain polymorphisms in the SERPINE1 gene, such as the 4G/4G genotype, may have higher PAI-1 levels and a higher predisposition to thrombotic events.

Cardiovascular Disease: PAI-1 is a well-established risk factor for cardiovascular diseases, including atherosclerosis and coronary artery disease. Elevated PAI-1 levels contribute to the formation of atherosclerotic plaques by inhibiting fibrinolysis and promoting inflammation. Increased PAI-1 expression is commonly seen in individuals with metabolic syndrome, obesity, and insulin resistance, all of which are risk factors for cardiovascular diseases.

Metabolic Disorders: PAI-1 levels are closely linked to metabolic conditions. Obesity, insulin resistance, and type 2 diabetes are associated with elevated PAI-1 expression. Adipose tissue is a major source of PAI-1, and its overexpression in obesity contributes to the prothrombotic state observed in these individuals. Elevated PAI-1 levels are also thought to play a role in the development of vascular complications in diabetes.

Cancer: Elevated PAI-1 expression is observed in various types of cancer, including breast, lung, and colorectal cancer. PAI-1 promotes tumor progression by influencing ECM remodeling, cell migration, and angiogenesis. High PAI-1 levels in tumors are often associated with a poor prognosis, as it facilitates the invasive and metastatic behavior of cancer cells.

Summary

SERPINE1 (PAI-1) is a key regulator of fibrinolysis and plays a significant role in maintaining the balance between clot formation and breakdown. Its ability to inhibit plasminogen activators (tPA and uPA) makes it crucial for regulating clot dissolution. Beyond its role in fibrinolysis, PAI-1 is involved in tissue remodeling, inflammation, and cancer progression. Elevated levels of PAI-1 are associated with thrombotic disorders, cardiovascular disease, metabolic syndrome, and cancer, making it a significant biomarker and potential therapeutic target for these conditions. Understanding the regulatory mechanisms of PAI-1 expression and function is critical for developing strategies to treat diseases associated with its dysregulation.