SERPINA3 - serpin family A member 3 |Elisa - Clia - Antibody - Protein

Background

SERPINA3, also known as alpha-1 antichymotrypsin (ACT), is a member of the serine protease inhibitor (serpin) superfamily. The SERPINA3 gene is located on chromosome 14 (14q32.13), in close proximity to other serpin genes, including SERPINA1, which encodes alpha-1 antitrypsin. SERPINA3 plays a crucial role in inhibiting the activity of certain proteases, particularly cathepsin G and chymotrypsin, enzymes involved in inflammation and immune responses. The protein encoded by SERPINA3 is predominantly synthesized in the liver, but it is also expressed in various other tissues, including the brain, lungs, and immune cells. SERPINA3 has been implicated in a variety of physiological and pathological processes, such as inflammation, tissue remodeling, and the acute phase response. It is also known for its association with neurodegenerative diseases, particularly Alzheimer's disease, where it is found in amyloid plaques.

Protein Structure

Alpha-1 antichymotrypsin (ACT) is a glycoprotein composed of approximately 423 amino acids and has a molecular weight of about 68 kDa. Similar to other serpins, the structure of SERPINA3 consists of three beta-sheets and several alpha-helices, with the reactive center loop (RCL) being a critical region for its inhibitory function. The RCL acts as a pseudo-substrate for target proteases. Upon interaction with a protease, the RCL is cleaved, leading to a significant conformational change in the protein. This change traps the protease in a covalently bound, inactive complex, thereby inhibiting its activity.

The glycosylation of ACT occurs at several asparagine residues, which are crucial for its stability, secretion, and function. Aberrant glycosylation or mutations that disrupt the folding of the protein can lead to the formation of dysfunctional SERPINA3, which has been linked to various diseases. Additionally, SERPINA3 contains several disulfide bonds that are essential for maintaining its structural integrity and inhibitory function.

Classification and Subtypes

SERPINA3 is classified within the serpin superfamily, which includes a large group of proteins that inhibit serine proteases. Specifically, SERPINA3 belongs to clade A of the serpin family, which also includes alpha-1 antitrypsin (SERPINA1) and corticosteroid-binding globulin (SERPINA6). While there are no major subtypes of SERPINA3, variations in the gene, such as single nucleotide polymorphisms (SNPs), can affect the protein's expression, function, and association with diseases.

Function and Biological Significance

The primary function of SERPINA3 is to inhibit serine proteases, with its main targets being chymotrypsin-like proteases, such as cathepsin G. Cathepsin G is a protease released by activated neutrophils during inflammation, and if not properly regulated, it can contribute to tissue damage by degrading extracellular matrix components. By inhibiting cathepsin G, SERPINA3 plays a protective role in controlling inflammation and preventing excessive tissue destruction.

Beyond its role in protease inhibition, SERPINA3 is involved in the acute phase response, a rapid systemic reaction to inflammation, infection, or injury. During the acute phase response, the levels of SERPINA3 in the blood increase significantly, which helps to modulate the inflammatory response and limit tissue damage.

SERPINA3 is also implicated in neuroinflammatory and neurodegenerative conditions. It has been found in the amyloid plaques of patients with Alzheimer's disease, suggesting a role in the pathogenesis of this condition. The presence of SERPINA3 in these plaques is thought to contribute to the chronic inflammatory state observed in Alzheimer's disease, which exacerbates neuronal damage and cognitive decline. Furthermore, SERPINA3 may influence the formation and stability of amyloid-beta aggregates, a hallmark of Alzheimer's disease pathology.

Clinical Issues

Mutations or dysregulation of SERPINA3 can lead to various clinical conditions, primarily related to inflammation and tissue damage. One of the most well-documented associations is with Alzheimer's disease. Increased levels of SERPINA3 have been observed in the brains of Alzheimer's patients, where it co-localizes with amyloid plaques. This association suggests that SERPINA3 may play a role in the inflammatory processes that contribute to the progression of neurodegenerative diseases.

In addition to Alzheimer's disease, SERPINA3 has been implicated in other inflammatory and autoimmune disorders. Elevated levels of SERPINA3 have been reported in conditions such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, and atherosclerosis, where it may contribute to the regulation of inflammation and tissue remodeling. In COPD, for example, SERPINA3 may help to counteract the proteolytic activity of enzymes like cathepsin G, thereby protecting lung tissue from damage.

Furthermore, SERPINA3 has been linked to certain cancers, where its expression can be altered. In some tumors, such as hepatocellular carcinoma and prostate cancer, increased levels of SERPINA3 have been observed, and it may play a role in tumor progression and metastasis by modulating the tumor microenvironment and influencing immune responses.

Summary

SERPINA3, or alpha-1 antichymotrypsin, is a serine protease inhibitor that plays a critical role in regulating protease activity, particularly during inflammation. Its function as an inhibitor of proteases like cathepsin G is essential for controlling inflammation and preventing tissue damage. SERPINA3 is also a key player in the acute phase response and has significant implications in neurodegenerative diseases, especially Alzheimer's disease, where it is found in amyloid plaques and may contribute to disease progression.

The dysregulation of SERPINA3 has been associated with a range of clinical conditions, including inflammatory diseases, neurodegeneration, and cancer. As research continues to unravel the complex roles of SERPINA3, it is becoming increasingly clear that this protein is a vital component of the body's defense mechanisms against protease-mediated tissue damage and inflammation. Understanding the molecular biology of SERPINA3 and its involvement in disease processes may lead to new therapeutic approaches for conditions characterized by excessive inflammation and protease activity.