Miranda, E. and Pérez, J. and Ekeowa, U.I. and Hadzic, N. and Kalsheker, N. and Gooptu, Bibek and Portmann, B. and Belorgey, D. and Hill, M. and Chambers, S. and Teckman, J. and Alexander, G.J. and Marciniak, S.J. and Lomas, D.A. (2010) A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency. Hepatology 52 (3), pp. 1078-1088. ISSN 0270-9139.
Abstract
Alpha(1)-antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (G1u342Lys) causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes. This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation-specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by alpha(1)-antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; a(1)-antitrypsin King's) identified in a 6-week-old boy who presented with prolonged jaundice. His334Asp a(1)-antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticuhun and show delayed secretion when compared to the wild-type M a(1)-antitrypsin. The 2C1 antibody recognizes polymers formed by Z and His334Asp trypsin despite the mutations directing their effects on different 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 alpha(1)-rantitrypsin. Conclusion: Z and shutter domain mutants of alpha(1)-antitrypsin form polymers with a shared epitope and so are likely to have a similar structure.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 01 Apr 2011 12:51 |
| Last Modified: | 02 Aug 2023 16:54 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/3245 |
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