Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications

, College of Physicians and Surgeons, Columbia University, NY

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Molecular Basis for Alpha1-ATD

Conformational changes that occur in the serpin molecules confer them with a great affinity for, and strong binding capacity to, their respective target protease. For example, antithrombin is said to be a "suicide substrate" for many of the pro-coagulant proteases such as Xa and IXa. Because of the precise structure/function relationship of the molecules, they are particularly susceptible to loss of function as a result of point mutations.

Mobility of the serpins. The phenotypic variants of the alpha1 protein are named to reflect the speed with which they migrate in an electric field at a pH between 4 and 5. For example, the normal M protein, which is present in over 90% of the population, migrates to an intermediate position, while the Z protein migrates slowest. The S form is intermediate in mobility as well.

Each allele at the alpha1-antitrypsin locus is codominantly expressed in the offspring, therefore those heterozygous for the deficiency express intermediate levels of serum protein. The most common form of the deficiency is PiZ (protease inhibitor Z) which is present in over 95% of those significantly affected. In these cases, the serum alpha1 concentration is approximately 15% of the normal PiM state.

After RNA transcription, the protein precursor is synthesized on the rough endoplasmic reticulum and subsequently undergoes posttranslational modification in the cisternae, where carbohydrate side chains are added. The mature protein is excreted after further modifications in the Golgi apparatus. The mature alpha1 protein is pleomorphic, with most variations in the protein chain compatible with normal function. Normal variations in the protein chain are compatible with normal function so long as they do not occur at sites that are critical for the correct tertiary folding of the molecule -- which is essential for the interaction with the specific protease.

Another molecular mechanism mediating alpha1-ATD is a deletion mutation. This event leads to a 5' shift in the reading frame, resulting in the production of a stop codon. The resulting truncated protein product has no biologic activity, a condition known as the null state. Individuals expressing such an abnormal variant of the alpha1 protein are not susceptible to liver disease, but emphysema invariably occurs.

Conformational changes in alpha1-AT. In PiZ (protease inhibitor, phenotype Z), the most common variant of this inherited condition resulting in a severe clinically relevant deficiency, a single amino acid substitution (Glu342 to Lys) affects the hinge region of the reactive loop of the protein. This mutation results in spontaneous insertion of the reactive site between the A sheets of other alpha1-AT molecules with subsequent polymerization. Although synthesis proceeds normally, polymerized alpha1-AT is not secreted and accumulates in the hepatocyte, where the molecule is made, leading to cirrhosis in some cases. Hepatic sequestration results in alpha1-AT serum levels of about 15% of normal. In addition to the abnormal storage effect, the alpha1-AT secreted by the liver has a reduced affinity for neutrophil elastase compared with the normal protein. Thus, alpha1-ATD is both a condition of abnormal storage and abnormal function of the anti-protease molecule.

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