This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation-specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by α1-antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; α1-antitrypsin King’s) identified in a 6-week-old boy who presented with prolonged jaundice. His334Asp α1-antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticulum and show delayed secretion when compared to the wild-type M α1-antitrypsin. The 2C1 antibody recognizes polymers formed by

Z and His334Asp α1-antitrypsin despite the mutations directing their effects C59 wnt chemical structure on different Fulvestrant cell line parts of the protein. This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of α1-antitrypsin. Conclusion: Z and shutter domain mutants of α1-antitrypsin form polymers with a shared epitope and so are likely to have a similar structure. HEPATOLOGY 2010 The serpinopathies are conformational diseases characterized by the polymerization and intracellular retention

of members of the serine protease inhibitor or serpin superfamily of proteins.1 The best known is α1-antitrypsin deficiency, with the most common severe deficiency allele being the Z mutation (Glu342Lys). This mutation results in the retention of ordered polymers of α1-antitrypsin as periodic acid Schiff positive inclusion bodies within the endoplasmic reticulum (ER) of hepatocytes.2 These inclusions predispose the individual homozygous for the Z variant of the α1-antitrypsin protease inhibitor (PI*Z) to neonatal hepatitis, cirrhosis, and rarely, hepatocellular carcinoma.3 Deficiency of circulating α1-antitrypsin results in early onset panlobular emphysema.4 The Z mutation of α1-antitrypsin

lies between the head of strand 5A and the base of the mobile reactive center loop5 (Fig. 1). Other mutations that cause α1-antitrypsin deficiency cluster around the shutter region of the protein (Fig. 1). In the classical model of serpin polymerization, these mutations are believed to open β-sheet A, giving rise to 上海皓元医药股份有限公司 a polymerogenic intermediate that has been termed M*.6, 7 The patent β-sheet A then accepts the reactive loop of a second α1-antitrypsin molecule to form a dimer, which can extend into chains of reactive center loop-β-sheet A polymers.2, 6, 8-12 The recent crystal structure of a dimer of another serpin, antithrombin, demonstrated a linkage between a β-hairpin of the reactive loop and strand 5A of one molecule and β-sheet A of another. This dimer was used as the basis of a novel model for the polymer in which helix I is unravelled and the proteins are linked by a β-hairpin containing the reactive center loop and strand 5A.