Alpha-1-antitrypsin Z variant protein (A1AT Z (also written as α1-AT Z or Z-AAT))

The **Alpha-1-antitrypsin Z variant protein** is a mutant form of the serine protease inhibitor alpha-1-antitrypsin (A1AT), resulting from a single amino acid substitution (Glu342Lys, E342K) in the SERPINA1 gene[5][3][9][8]. This mutation destabilizes the protein fold, leading to its polymerization and accumulation in hepatocytes, causing liver disease, while a deficiency of active A1AT in the plasma leads to unopposed neutrophil elastase activity and progressive lung damage (emphysema)[4][3][9][8]. The Z variant is the most common pathological allele in alpha-1 antitrypsin deficiency, especially among Northern Europeans, and explains both hepatic and pulmonary manifestations of the disease[3][5][4][8]. Therapeutically, the Z variant protein is a principal target for replacement therapies and experimental small molecules or peptides designed to prevent polymerization or restore function[6][2]. It is considered a classic example of a conformational disease/disease of protein misfolding[3][5][11].

Other names

Z alpha-1-antitrypsinZ variant of alpha-1-antitrypsinGlu342Lys alpha-1-antitrypsinZ-AATα1-AT Z variantSERPINA1 Z variantPI*Z (Protease Inhibitor Z)

Protein augmentation/replacement: supplementing functional A1AT to restore protease inhibition Small molecule stabilization: stabilizing native protein fold to prevent polymerization and hepatic accumulation Inhibition of mutant Z variant polymerization Improvement of protein secretion from hepatocytes