Suppression of the facile latency transition of α 1-antitrypsin variant M malton by stabilizing mutations

Abstract

Many genetic variants of α 1-antitrypsin (α 1AT) are associated with early onset emphysema and liver cirrhosis. We previously found that although the stability and inhibitory activity of the human α 1AT variant M malton (Phe52-deleted) are comparable to those of wild-type α 1AT, the M malton variant spontaneously undergoes a conformational change to a more stable, inactive, latent form under physiological conditions. Here, we show that insertion of an exogenous peptide having a sequence corresponding to the first strand of β-sheet C (s1C) is facilitated in M malton α 1AT, suggesting that the endogenous s1C and reactive center loop are easily released from β-sheet C, thus promoting latency conversion. When additional stabilizing mutations were introduced into M malton α 1AT, they suppressed the conformational defect of this variant: the latency transition was greatly retarded, presumably by strengthening the interactions between s1C and β-sheet C.