PI
MIM.107400 14q32.1
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Definition: Alpha-1-antitrypsin is a protease inhibitor, deficiency of which is associated with emphysema and liver disease. The protein is encoded by a gene (PI) located on the distal long arm of chromosome 14.
alpha 1-Antitrypsin or ?1-antitrypsin (A1AT) is a glycoprotein and generally known as serum trypsin inhibitor. The correct name, however, is alpha-1 proteinase inhibitor (A1PI) because it is a serine protease inhibitor (serpin) inhibiting a wide variety of proteases.
It protects tissues from enzymes of inflammatory cells, especially elastase, and is present in human blood at 1.5 - 3.5 gram/liter, but the concentration can rise manyfolds upon acute inflammation.
In its absence, elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as panlobular emphysema leading finally to COPD (chronic obstructive pulmonary disease).
A1AT is a 52 kDa serine protease inhibitor, and is a member of serpins. Most serpins inactivate enzymes by binding to them covalently, requiring very high levels to perform their function. Like all serine protease inhibitors (serpins), A1AT has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins which can polymerise and accumulate in the liver, causing an infantile hepatic cirrhosis.
Conformational anomalies of A1AT
Members of the serpin, or serine proteinase inhibitor, superfamily, such as alpha1-antitrypsin (A1AT), undergo a striking conformational transition to inhibit their target proteinase.
After docking, the target proteinase is inactivated by movement from the upper to the lower pole of the protein. This is associated with the insertion of the reactive loop of the serpin as an extra strand into beta-sheet A.
The inhibitory mechanism might be triggered spontaneously by certain point mutations, which result in diseases known as the serpinopathies.
The best characterized of these mutations is the Z variant of alpha1-antitrypsin (a E342K substitution at P17 (17 residues proximal to the P1 residue at the reactive centre) at the proximal hinge of the molecule (between beta-sheet A and the loop containing the reactive centre) or mutations in the shutter domain that open beta-sheet A to favour partial loop insertion and the formation of an unstable intermediate (M*).
The open beta-sheet A can either accept the loop of another molecule to form a dimer, which then extends into polymers, or its own loop to form a latent conformation.
Conformational instability of the serpins can also result from mutations in the distal hinge region.
Pathology
Deficiency of 1-antitrypsin was clinically described for the first time in 1963 by Carl-Bertil Laurell and Sten Eriksson, who noted an absence of the 1-band on electrophoresis of the serum of some patients with lung disease.
More then 70 naturally occurring variants of 1-antitrypsin have been described and characterized by their migration on isolelectric focusing gels.
The PI Z mutation
One in 2,000 individuals from northern Europe is homozygous for the severe Z mutation (a E342K substitution), with plasma levels that are 10?15% of those present in individuals with the normal M allele.
The Z mutation results in the accumulation of alpha1-antitrypsin as periodic acid schiff (PAS)-positive inclusions in the rough endoplasmic reticulum of the liver. These inclusions cause transient juvenile hepatitis in 90% of homozygotes; 1?2% of these individuals will also develop cirrhosis and be at risk of developing hepatocellular carcinoma.
Panlobular emphysema
The main function of alpha1-antitrypsin is to protect the tissues, and especially the elastic tissue of the lungs, against the enzyme neutrophil elastase. The lack of circulating alpha1-antitrypsin results in an imbalance between enzymes and inhibitors in the lung, which causes early-onset panlobular emphysema (therefore explaining why this deficiency was first recognized in individuals with lung disease).
germline mutations in alpha1-antitrypsin deficiency (A1AT deficiency)
References
Elliott PR, Abrahams JP, Lomas DA. Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation. J Mol Biol. 1998 Jan 23;275(3):419-25. PMID: 9466920