SERPING1 - serpin family G member 1 |Elisa - Clia - Antibody - Protein

Background

SERPING1, also known as C1 esterase inhibitor (C1-INH), is a serine protease inhibitor that plays a critical role in regulating the complement system, a part of the immune response. SERPING1 is primarily responsible for controlling the activation of the C1 complex in the classical pathway of complement activation. Beyond complement regulation, it also inhibits several other proteases involved in the coagulation, fibrinolytic, and kinin-generating systems. SERPING1 mutations or deficiencies are strongly linked to hereditary angioedema (HAE), a potentially life-threatening condition characterized by uncontrolled swelling.

SERPING1 is an important therapeutic target in diseases where inappropriate immune activation or excessive protease activity leads to tissue damage or inflammation. It is mainly synthesized in the liver and secreted into the bloodstream, where it circulates and exerts its regulatory effects.

Protein Structure

The SERPING1 protein is a glycoprotein composed of 478 amino acids with a molecular mass of approximately 105 kDa. It belongs to the serpin (serine protease inhibitor) superfamily, which includes proteins involved in regulating various proteolytic processes, including blood coagulation, fibrinolysis, and immune responses.

The structure of SERPING1 is characterized by its core serpin fold, a conserved structural motif consisting of three β-sheets and multiple α-helices. Its reactive center loop (RCL), a crucial feature of serpins, acts as a bait for target proteases. Upon interaction with a protease, SERPING1 undergoes a conformational change that traps the protease in a covalent complex, rendering it inactive.

The functional regions of SERPING1 include:

• Reactive center loop (RCL): This loop region interacts with the protease’s active site and undergoes a large structural rearrangement upon binding, forming an irreversible complex.
• Heparin-binding domain: SERPING1 also has a domain that binds to glycosaminoglycans such as heparin, which enhances its inhibitory activity. Heparin accelerates the interaction between SERPING1 and its protease targets, increasing the efficiency of inhibition.
• Glycosylation sites: SERPING1 has several N-linked glycosylation sites that are essential for its stability, solubility, and interaction with other molecules in the plasma.

Classification and Subtypes

SERPING1 is classified under the serpin family, which consists of proteins with broad inhibitory functions against serine proteases. It is part of clade G (clade I in some nomenclatures), which includes other inhibitors of proteolytic cascades involved in immunity and inflammation.

There are no known functional subtypes of SERPING1, but various mutations and polymorphisms of the SERPING1 gene have been identified, especially in individuals with hereditary angioedema (HAE). These genetic variants can lead to either a quantitative or functional deficiency of C1-INH, which directly impacts the regulation of the complement system and other related proteolytic pathways.

Function and Biological Significance

SERPING1, primarily known as C1-INH, has several crucial functions in regulating inflammation, immune responses, and blood clotting:

1. Regulation of the Classical Complement Pathway: SERPING1’s primary function is to inhibit the C1r and C1s proteases in the C1 complex, a key component of the classical complement activation pathway. The complement system is an essential part of innate immunity, and its activation leads to the destruction of pathogens, the recruitment of immune cells, and the promotion of inflammation. By inhibiting C1r and C1s, SERPING1 prevents the uncontrolled activation of this system, ensuring that immune responses are appropriately controlled and do not lead to excessive inflammation or tissue damage.
2. Inhibition of the Kallikrein-Kinin System: In addition to its role in complement regulation, SERPING1 also inhibits plasma kallikrein, a protease that plays a crucial role in the generation of bradykinin, a potent vasodilator that increases vascular permeability. By inhibiting kallikrein, SERPING1 prevents excessive bradykinin production, which is particularly important in preventing the inappropriate vascular permeability and swelling seen in conditions such as hereditary angioedema.
3. Regulation of the Coagulation and Fibrinolytic Systems: SERPING1 also inhibits certain proteases involved in the coagulation and fibrinolytic systems, including factor XIIa and plasmin. By regulating these proteases, SERPING1 helps to maintain the balance between clot formation and clot breakdown, preventing both excessive bleeding and inappropriate clotting.
4. Prevention of Hereditary Angioedema (HAE): The most well-known clinical condition associated with SERPING1 deficiency is hereditary angioedema (HAE), a disorder characterized by recurrent episodes of severe swelling (angioedema) in various parts of the body, including the skin, gastrointestinal tract, and airways. The swelling in HAE is caused by excessive bradykinin production due to unregulated kallikrein activity, which results from a lack of functional C1-INH. SERPING1 deficiency can be either quantitative (insufficient production of the protein) or functional (the protein is produced but cannot effectively inhibit its target proteases).

Clinical Issues

Mutations or deficiencies in the SERPING1 gene lead to hereditary angioedema (HAE), which comes in three types:

1. Type I HAE: This is the most common form and is caused by a quantitative deficiency of C1-INH. In these patients, SERPING1 is either not produced or produced in insufficient amounts, leading to unregulated complement and kallikrein activity.
2. Type II HAE: In this form, C1-INH is produced in normal quantities but is functionally defective, meaning it cannot inhibit its target proteases effectively.
3. Type III HAE: A less common form of the disease, which is not associated with C1-INH deficiency but rather with mutations in other components of the kallikrein-kinin system. However, it is included in discussions of HAE because of the similarity in clinical presentation.

Other clinical issues related to SERPING1 dysfunction include:

• Acquired angioedema (AAE): This condition, which resembles HAE, occurs in individuals without a family history of the disease. It is typically associated with underlying conditions, such as lymphoproliferative disorders or autoimmune diseases, which lead to consumption or inactivation of C1-INH.
• Increased Susceptibility to Infections and Autoimmune Diseases: Given SERPING1’s role in regulating the complement system, deficiencies in this protein can lead to an increased risk of infections and autoimmune conditions due to dysregulated complement activation and inflammation.

Therapeutic Applications

SERPING1 has been a key therapeutic target for the treatment of hereditary angioedema. Several therapies are available or under development to address C1-INH deficiency or dysfunction:

1. C1-INH Replacement Therapy: This involves the administration of purified C1-INH protein, either from human plasma or recombinant sources, to patients with HAE. These therapies provide functional C1-INH to restore normal complement and kallikrein regulation.
2. Bradykinin Receptor Antagonists: Since excessive bradykinin production is responsible for the symptoms of HAE, antagonists of the bradykinin B2 receptor can be used to block the effects of bradykinin and prevent or treat angioedema attacks.
3. Kallikrein Inhibitors: Drugs that directly inhibit kallikrein can be used to prevent bradykinin generation and reduce the frequency and severity of angioedema attacks in HAE patients.

Summary

SERPING1, or C1 esterase inhibitor (C1-INH), is a critical regulator of the complement system, the coagulation cascade, and the kallikrein-kinin system. By inhibiting these proteases, SERPING1 helps to control inflammation, prevent excessive clotting, and maintain the integrity of blood vessels. Mutations or deficiencies in SERPING1 lead to hereditary angioedema (HAE), a condition characterized by recurrent episodes of swelling. Treatment strategies for HAE include C1-INH replacement therapy, bradykinin receptor antagonists, and kallikrein inhibitors, all of which aim to restore the balance of protease activity and prevent excessive swelling. Given its role in multiple biological pathways, SERPING1 remains a key target for therapeutic intervention in diseases involving excessive protease activity or dysregulated immune responses.