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  • Title: Suppression of the facile latency transition of alpha(1)-antitrypsin variant M(malton) by stabilizing mutations.
    Author: Jung CH, Chae YK, Im H.
    Journal: Biochem Biophys Res Commun; 2004 Dec 17; 325(3):744-50. PubMed ID: 15541353.
    Abstract:
    Many genetic variants of alpha(1)-antitrypsin (alpha(1)AT) are associated with early onset emphysema and liver cirrhosis. We previously found that although the stability and inhibitory activity of the human alpha(1)AT variant M(malton) (Phe52-deleted) are comparable to those of wild-type alpha(1)AT, 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 beta-sheet C (s1C) is facilitated in M(malton) alpha(1)AT, suggesting that the endogenous s1C and reactive center loop are easily released from beta-sheet C, thus promoting latency conversion. When additional stabilizing mutations were introduced into M(malton) alpha(1)AT, they suppressed the conformational defect of this variant: the latency transition was greatly retarded, presumably by strengthening the interactions between s1C and beta-sheet C.
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