Serpins: a1-antitrypsin

The suicide pact

Serpins, nicknamed suicide inhibitors, have developed a unique means of blocking protease activity. They employ a mechanism that covalently traps their targets by undergoing an irreversible conformational change, effectively destroying both the protease and themselves into the bargain.

a1-Antitrypsin contains an exposed reactive centre loop (RCL) that projects from the body of the protein, acting as ‘bait’ for the protease to attack. Once the protease binds the serpin and cleaves the RCL, the RCL undergoes a large conformational change, resulting in the insertion of the RCL within the interior of the serpin protein, thereby trapping the covalently bound protease. The energy to drive this rearrangement comes from within the serpin itself. While most proteins fold into their most stable state, the native conformation of a1-antitrypsin is said to be ‘metastable’, or stressed. The binding of the target protease triggers the conversion of the serpin to its most stable, or relaxed, state. In this way, the serpin is acting as a kinetic trap, much in the same way as a mousetrap works: the molecule is under conformational constraint causing it to snap shut upon binding to the target. Once the serpin is in its most stable state, covalently bound to the protease, the protease is unable to be released from the ‘jaws’ of the serpin, locked in a fatal embrace.

Serpinopathy, when things go wrong

When genetic mutations cause a deficiency of one of the many plasma serpins, diseases can result, which are collectively known as serpinopathies. These include diseases such as blood clotting disorders, emphysema, cirrhosis, and dementia. In the case of a1-antitrypsin, a deficiency of this protein can cause liver and lung disease, as well as a predisposition to certain cancers. For example, a mutation in the a1-antitrypsin gene, known as the Z allele (Glu342Lys), disrupts the structure of the protein, causing a1-antitrypsin polypeptides to link together to form inactive polymers. These polymers accumulate in the liver cells, where most of the a1-antitrypsin is produced. This overload of a1-antitrypsin causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. In addition, the lack of a1-antitrypsin in plasma exposes lung tissue to proteolytic attack by neutrophil elastase, resulting in excessive degradation of elastin fibres that eventually causes pulmonary emphysema. Cigarette smoking can exasperate emphysema in a1-antitrypsin-deficient patients, because it stimulates neutrophil activation and the release of neutrophil elastase into the lower respiratory tract. The tissue damage caused by the imbalance between neutrophil elastase and a1-antitrypsin can create a favourable environment for carcinogenesis and tumour progression, hence a1-antitrypsin-deficiency is associated with an increased risk of liver cancer, bladder cancer, gall bladder cancer, malignant lymphoma and lung cancer.

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