The 'deficiency' group of α1-antitrypsin (α1AT) alleles is characterized by α1AT genes that code for α1AT present in serum but in amounts insufficient to protect the lower respiratory tract from progressive destruction by its burden of neutrophil elastase. M(procida), a rare α1AT allele associated with α1AT serum levels less than 10 mg/dl (normal 150-350 mg/dl), codes for an α1AT molecule that focuses on immobilized pH gradient isolelectric gels slightly cathodal to the common normal M1(Val213) protein. On a per molecule basis, M(procida) has a mildly reduced function as an inhibitor, with an association rate constant for human neutrophil elastase of 7.0 ± 0.1 x 106 M-1 s-1 (normal M1 (Val213) 9.3 ± 0.8 x 106, p<0.01). The M(procida) molecule behaves normally in vivo with a half-life similar to normal M1 α1AT molecules. Restriction endonuclease mapping demonstrates that the cloned M(procida) gene was grossly intact. Sequencing of all the exons, exon-intron junctions, and the major promoter region demonstrated M(procida) to be identical to the M1(Val213) gene except for a single base substitution in exon II coding for amino acid 41 of the mature protein (M1(Val213) Leu41 CTG→M(procida) Pro41 CCG). Usefully, the coding sequence of the α1AT residues 40-41 is recognized by the restriction endonuclease PvuII so that using a probe corresponding to this region of exon II, the M(procida) mutation can be rapidly identified by Southern analysis. Evaluation of the crystallographic structure of α1AT suggests the Leu41 to Pro41 mutation may disrupt α-helix A in the region of Pro21-Ser45, suggesting the possibility that the α1AT M(procida) molecule is unstable and degraded intracellularly prior to secretion.
|Number of pages||7|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - 1 Jan 1988|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology