Loop-sheet polymerization: the mechanism of alpha1-antitrypsin deficiency.
Alpha1-antitrypsin deficiency results from point mutations that distort the structure of the protein to allow a unique protein-protein interaction that we have termed loop-sheet polymerization. Polymers of Z alpha1-antitrypsin accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha1-antitrypsin homozygote to emphysema. This polymerization process also occurs in variants of other members of the serine proteinase inhibitor (serpin) superfamily, antithrombin, C1-inhibitor and alpha1-antichymotrypsin in association with thrombosis, angiooedema and chronic obstructive pulmonary disease respectively, and we have recently shown that it underlies a novel inclusion body dementia. Understanding this mechanism of polymerization allows rational drug design to block the protein-protein linkage and so ameliorate the associated disease.
Lomas
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DA
Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, UK. dal16@cam.ac.uk
D000799:Angioedema / Q000209:etiology; D003704:Dementia / Q000209:etiology; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000209:etiology; D017354:Point Mutation / Q000235:genetics; D011108:Polymers; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012907:Smoking / Q000009:adverse effects; D013927:Thrombosis / Q000209:etiology; D000515:alpha 1-Antitrypsin / Q000737:chemistry*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000628:therapy
D011108:Polymers; D000515:alpha 1-Antitrypsin