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

M Yamasaki, TJ Sendall, MC Pearce, JC Whisstock… - EMBO …, 2011 - embopress.org
M Yamasaki, TJ Sendall, MC Pearce, JC Whisstock, JA Huntington
EMBO reports, 2011embopress.org
α1‐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 domain swapping the carboxy‐terminal …
α1‐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 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 α1AT in vivo.
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