SERPINA1 - serpin family A member 1 |Elisa - Clia - Antibody - Protein

Background

The SERPINA1 gene, commonly known as alpha-1 antitrypsin (A1AT), encodes a protein that plays a crucial role in protecting tissues from enzymes of inflammatory cells, particularly neutrophil elastase. This gene is part of the serine protease inhibitor (serpin) superfamily and is located on chromosome 14 (14q32.13). Alpha-1 antitrypsin is primarily synthesized in the liver, although it is also produced in smaller quantities by other tissues, including the lungs, intestines, and kidneys. The protein encoded by SERPINA1 is a glycoprotein that circulates in the blood and functions as a major inhibitor of proteases, especially neutrophil elastase, which, if left unchecked, can degrade elastin and other extracellular matrix components, leading to tissue damage.

Protein Structure

Alpha-1 antitrypsin is a glycoprotein consisting of 394 amino acids and has a molecular weight of approximately 52 kDa. The protein is composed of three major regions: the reactive center loop (RCL), the A-sheet, and the B-sheet. The RCL is crucial for its function as it acts as a bait for proteases. The serpin undergoes a conformational change upon interaction with its target protease, forming a stable complex that inactivates the protease. This mechanism is vital for controlling the activity of neutrophil elastase in the lungs, where the enzyme is released during inflammation.

The structure of A1AT is stabilized by the presence of several disulfide bonds and glycosylation sites, which are important for its function and secretion. The glycosylation of A1AT occurs at three asparagine residues (N46, N83, and N247), and this post-translational modification is critical for its stability and interaction with proteases. Any mutations that affect the glycosylation sites or the overall folding of the protein can lead to misfolding and aggregation, which are associated with various diseases, particularly alpha-1 antitrypsin deficiency.

Classification and Subtypes

SERPINA1 belongs to the serpin family, a large group of proteins that share a common structure and function as inhibitors of serine proteases. Within the serpin family, SERPINA1 is classified as a clade A serpin, which primarily targets elastase. However, variations in the SERPINA1 gene can result in different phenotypes with varying levels of functional A1AT. These phenotypes are classified based on the electrophoretic mobility of the protein, with the most common being the M (normal), Z (deficient), and S (intermediate deficiency) variants.

• M variant (normal): This variant is associated with normal levels of A1AT in the blood and normal function.
• Z variant (deficient): The Z variant results from a single point mutation (Glu342Lys) and leads to the production of a misfolded protein that accumulates in the liver, leading to reduced levels of functional A1AT in the blood and an increased risk of lung and liver diseases.
• S variant (intermediate deficiency): The S variant (Glu264Val) also results in reduced levels of A1AT but is generally associated with a milder form of deficiency compared to the Z variant.

Other rare variants exist, and these can lead to a range of functional outcomes from normal activity to complete deficiency, depending on the specific mutation.

Function and Biological Significance

The primary function of alpha-1 antitrypsin is to inhibit neutrophil elastase, thereby protecting tissues, particularly in the lungs, from enzyme-mediated damage. Neutrophil elastase is a potent protease released by activated neutrophils during inflammation. If not properly regulated, it can degrade elastin, leading to the destruction of alveolar walls and the development of emphysema, a hallmark of chronic obstructive pulmonary disease (COPD).

Alpha-1 antitrypsin also inhibits other proteases, including proteinase 3 and cathepsin G, further contributing to its protective role in tissues. Beyond its protease inhibitory function, A1AT has been shown to have anti-inflammatory and immunomodulatory properties, which are important in controlling the inflammatory response and preventing excessive tissue damage.

Clinical Issues

The most significant clinical condition associated with SERPINA1 is alpha-1 antitrypsin deficiency (AATD), a genetic disorder characterized by low levels of A1AT in the blood. AATD is a major risk factor for developing COPD, especially emphysema, and liver disease, including cirrhosis and hepatocellular carcinoma. The condition is particularly severe in individuals with the ZZ genotype, who have significantly reduced levels of functional A1AT due to the accumulation of misfolded protein in the liver.

Patients with AATD may present with respiratory symptoms, such as shortness of breath, chronic cough, and wheezing, often mimicking other respiratory conditions like asthma or smoking-related COPD. In the liver, the accumulation of misfolded A1AT can lead to neonatal jaundice, hepatitis, and progressive liver fibrosis, potentially resulting in cirrhosis or liver cancer.

Diagnosis of AATD involves measuring serum levels of A1AT, genotyping to identify specific SERPINA1 mutations, and assessing liver function. Treatment strategies for AATD include augmentation therapy with intravenous A1AT to increase circulating levels of the protein, as well as standard treatments for COPD and liver disease. For individuals with advanced liver disease, liver transplantation may be necessary.

Summary

The SERPINA1 gene, encoding alpha-1 antitrypsin, is a critical component of the body's defense against protease-mediated tissue damage, particularly in the lungs. Its role in inhibiting neutrophil elastase protects the lung's elastin and prevents the development of emphysema and other forms of COPD. Variants in the SERPINA1 gene can lead to alpha-1 antitrypsin deficiency, a condition associated with a significantly increased risk of lung and liver diseases. Understanding the molecular biology of SERPINA1 and its protein product has been crucial in developing diagnostic and therapeutic strategies for managing AATD and its associated complications. Continued research into the role of A1AT in inflammation and tissue protection may uncover new therapeutic approaches for a range of inflammatory and protease-related diseases.