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Molecular basis of ?1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer.

ABSTRACT: ?(1)-Antitrypsin (?1AT) deficiency is a disease with multiple manifestations, including cirrhosis and emphysema, caused by the accumulation of stable polymers of mutant protein in the endoplasmic reticulum of hepatocytes. However, the molecular basis of misfolding and polymerization remain unknown. We produced and crystallized a trimeric form of ?1AT that is recognized by an antibody specific for the pathological polymer. Unexpectedly, this structure reveals a polymeric linkage mediated by domain swapping the carboxy-terminal 34 residues. Disulphide-trapping and antibody-binding studies further demonstrate that runaway C-terminal domain swapping, rather than the s4A/s5A domain swap previously proposed, underlies polymerization of the common Z-mutant of ?1AT in vivo.

SUBMITTER: Yamasaki M

PROVIDER: S-EPMC3185345 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Molecular basis of α1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer.

Yamasaki Masayuki M Sendall Timothy J TJ Pearce Mary C MC Whisstock James C JC Huntington James A JA

EMBO reports 20110930 10

α(1)-Antitrypsin (α1AT) deficiency is a disease with multiple manifestations, including cirrhosis and emphysema, caused by the accumulation of stable polymers of mutant protein in the endoplasmic reticulum of hepatocytes. However, the molecular basis of misfolding and polymerization remain unknown. We produced and crystallized a trimeric form of α1AT that is recognized by an antibody specific for the pathological polymer. Unexpectedly, this structure reveals a polymeric linkage mediated by domai ...[more]

PMID: 21909074

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