title: Suppression of the facile latency transition of alpha(1)-antitrypsin variant M(malton) by stabilizing mutations.
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.
authors.affiliation: Department of Molecular Biology and Applied Chemistry, Degenerative Protein Research Center, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea.
authors.forename: Chan-Hun
authors.initials: CH
authors.lastname: Jung
authors.forename: Young Kee
authors.initials: YK
authors.lastname: Chae
authors.forename: Hana
authors.initials: H
authors.lastname: Im
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D016297:Mutagenesis, Site-Directed; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics*
chemical_list: D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase