SERPINA10 - serpin family A member 10 |Elisa - Clia - Antibody - Protein

Background

SERPINA10 is a gene encoding the protein Z-dependent protease inhibitor (ZPI), which is a member of the serpin (serine protease inhibitor) superfamily. The SERPINA10 gene is located on chromosome 14q32.1 and plays a critical role in the regulation of coagulation, specifically by inhibiting factors involved in the blood clotting cascade. ZPI is unique among the serpin family members because its inhibitory activity is modulated by the presence of protein Z, a cofactor that enhances its ability to inhibit coagulation factors. The understanding of SERPINA10 is essential in the context of hemostasis and thrombosis, as abnormalities in its function can lead to a predisposition to thrombotic disorders.

Protein Structure

The protein encoded by SERPINA10, ZPI, is a glycoprotein consisting of approximately 442 amino acids with a molecular weight of around 72 kDa. Like other serpins, ZPI has a highly conserved structure characterized by three β-sheets, eight to nine α-helices, and a reactive center loop (RCL). The RCL is the most critical part of the serpin structure because it serves as a bait for target proteases. When a protease attacks the RCL, it forms a covalent bond with the serpin, which undergoes a conformational change that traps the protease in a stable, inactive complex.

ZPI is glycosylated at multiple sites, which is important for its stability and function. The glycosylation helps the protein maintain its proper folding and circulatory half-life. Additionally, ZPI contains a heparin-binding site, which is crucial for its interaction with heparin, a glycosaminoglycan that enhances the inhibitory activity of ZPI against coagulation factors. The interaction between ZPI and protein Z is also dependent on specific domains within the ZPI structure, which allows it to effectively inhibit its target proteases.

Classification and Subtypes

SERPINA10 belongs to the serpin superfamily, which is a large group of proteins that share a common structure and function as protease inhibitors. The serpin family is classified into multiple clades based on sequence homology and function. SERPINA10 falls under the clade A of serpins, which includes other well-known serpins like α1-antitrypsin (SERPINA1) and antithrombin (SERPINC1).

Within its clade, SERPINA10 is unique due to its dependence on protein Z for full activity. Unlike other serpins that typically inhibit serine proteases directly, ZPI's inhibitory function is significantly enhanced by the presence of protein Z, which allows it to specifically inhibit factor Xa and factor XIa in the coagulation cascade. There are no known subtypes or isoforms of SERPINA10, but polymorphisms within the gene can affect its function and have been linked to various clinical conditions.

Function and Biological Significance

SERPINA10 plays a pivotal role in the regulation of the blood coagulation process. Its primary function is to inhibit factor Xa in the presence of protein Z and to a lesser extent, inhibit factor XIa. Factor Xa is a crucial enzyme in the coagulation cascade, responsible for the conversion of prothrombin to thrombin, which subsequently leads to the formation of fibrin clots. By inhibiting factor Xa, ZPI helps to regulate thrombin generation and prevent excessive clot formation, which is vital for maintaining the balance between bleeding and clotting.

The interaction between ZPI and protein Z is critical for its function. Protein Z acts as a cofactor, enhancing the inhibitory effect of ZPI on factor Xa by approximately 1000-fold. This interaction ensures that ZPI effectively controls coagulation under physiological conditions, preventing the risk of thrombosis.

ZPI also inhibits factor XIa, another enzyme involved in the intrinsic pathway of coagulation. Although the inhibition of factor XIa by ZPI is less pronounced than that of factor Xa, it still contributes to the regulation of clot formation, particularly in conditions where the intrinsic pathway is activated.

The biological significance of SERPINA10 extends beyond its role in coagulation. It is also involved in inflammatory processes, where its ability to modulate protease activity can influence the inflammatory response. Dysregulation of SERPINA10 has been implicated in several thrombotic disorders, highlighting its importance in maintaining vascular homeostasis.

Clinical Issues

Mutations and polymorphisms in the SERPINA10 gene have been associated with an increased risk of thrombotic disorders, particularly venous thromboembolism (VTE). VTE includes conditions such as deep vein thrombosis (DVT) and pulmonary embolism (PE), which are characterized by the formation of blood clots in the veins. Deficiency or dysfunction of ZPI can lead to uncontrolled factor Xa activity, resulting in excessive thrombin generation and an increased risk of clot formation.

Several studies have identified specific genetic variants in SERPINA10 that are associated with a predisposition to thrombosis. For example, a polymorphism known as G-34A in the promoter region of SERPINA10 has been linked to reduced expression of ZPI and an increased risk of VTE. Other variants may affect the interaction between ZPI and protein Z, further contributing to the risk of thrombotic events.

In addition to genetic factors, acquired conditions such as liver disease, where the synthesis of serpins is impaired, can also lead to ZPI deficiency and an increased risk of thrombosis. Conversely, elevated levels of ZPI have been observed in certain inflammatory conditions, where it may contribute to the modulation of the inflammatory response.

The role of SERPINA10 in cancer is also being investigated, as the coagulation cascade is often dysregulated in malignancies. Elevated thrombin generation, partly due to altered ZPI function, has been implicated in the hypercoagulable state observed in cancer patients, which increases their risk of thromboembolic complications.

Summary

SERPINA10 encodes the protein Z-dependent protease inhibitor (ZPI), a critical regulator of the coagulation cascade. ZPI inhibits factor Xa and factor XIa in the presence of protein Z, playing a key role in preventing excessive clot formation and maintaining hemostatic balance. The protein structure of ZPI, characterized by the conserved serpin fold and reactive center loop, is essential for its inhibitory function. Genetic variations in SERPINA10 can predispose individuals to thrombotic disorders, making it a significant focus of clinical research. Understanding the regulation and function of SERPINA10 is vital for developing therapeutic strategies to manage thrombosis and related conditions.