EMDB

ELA2

The ELA2 gene encodes the enzyme neutrophil elastase, which is a serine protease found in the azurophilic granules of neutrophils. Neutrophil elastase plays a crucial role in the innate immune response by degrading various proteins, including those of invading microorganisms, and is involved in the regulation of inflammation.

Structure

Neutrophil elastase is a member of the chymotrypsin family of serine proteases. The enzyme is synthesized as a preproenzyme, which is then processed to its mature form. The mature enzyme consists of a single polypeptide chain with a molecular weight of approximately 29 kDa. The active site of neutrophil elastase contains the catalytic triad of serine, histidine, and aspartate, which is characteristic of serine proteases.

Function

Neutrophil elastase is primarily involved in the degradation of extracellular matrix proteins, such as elastin, collagen, and fibronectin, during the inflammatory response. It also degrades bacterial virulence factors, contributing to the antimicrobial activity of neutrophils. Additionally, neutrophil elastase can modulate the activity of cytokines and chemokines, influencing the recruitment and activation of other immune cells.

Clinical Significance

Mutations in the ELA2 gene are associated with several human diseases, including severe congenital neutropenia (SCN) and cyclic neutropenia. These conditions are characterized by low levels of neutrophils, leading to increased susceptibility to infections. Neutrophil elastase is also implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD) and cystic fibrosis, where excessive activity of the enzyme contributes to tissue damage and inflammation.

Regulation

The activity of neutrophil elastase is tightly regulated by endogenous inhibitors, such as alpha-1 antitrypsin (AAT) and secretory leukocyte protease inhibitor (SLPI). These inhibitors prevent excessive proteolytic activity and protect tissues from damage. Dysregulation of neutrophil elastase activity, due to either genetic mutations or imbalances in inhibitor levels, can lead to pathological conditions.

Research and Therapeutic Implications

Research into the ELA2 gene and neutrophil elastase has led to the development of therapeutic strategies aimed at modulating its activity. Inhibitors of neutrophil elastase are being investigated as potential treatments for diseases such as COPD and cystic fibrosis. Gene therapy approaches are also being explored to correct mutations in the ELA2 gene in patients with congenital neutropenia.

Also see

• Neutrophil
• Serine protease
• Alpha-1 antitrypsin
• Congenital neutropenia
• Chronic obstructive pulmonary disease