Structural basis of human alpha-1-antitrypsin deficiency

Abstract

Two common variants, S and Z, of alpha-1-antitrypsin result in respectively a mild and severe circulating deficiency which predisposes towards the development of emphysema. A feature unique to the Z variant is the impaired secretion from the hepatocyte resulting in intra-cellular accumulation of insoluble, partially glycosylated antitrypsin. Peptide mapping techniques revealed that the S protein differed from the normal by the substitution of a glutamic acid by a valine residue, and the circulating Z protein differed from the normal by the substitution of a different glutamic acid by a lysine residue. Cyanogen bromide fragmentation of antitrypsin gave about ten fragments one of which contained the S and Z mutation sites. This fragment of 109 residues was sequenced and was large enough to allow a computer prediction of secondary structure. The S protein mutation site is predicted to be on a hydrophilic aspect of an alpha-helical section. Hence the presence of the new valine could result in incorrect folding or aggregation of the nascent protein to give intra-cellular degradation and decreased cellular export. The Z mutation has introduced a new lysine adjacent to another lysine in a position of the molecule that is likely to be externally situated and in a non-helical region. Paired basic residues are known to act as molecular markers for protein modification. The pathogenesis of the Z deficiency would be explicable by the new paired basic residues competing with an earlier homologous binding site at the rough endoplasmic reticulum level. Some of the Z protein will be processed but much of it will be arrested at the stage of incomplete glycosylation.