Molecular Mechanism of Z α1-Antitrypsin Deficiency.
Carrell, Robin W
The Journal of biological chemistry
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Huang, X., Zheng, Y., Zhang, F., Wei, Z., Wang, Y., Carrell, R. W., Read, R., et al. (2016). Molecular Mechanism of Z α1-Antitrypsin Deficiency.. The Journal of biological chemistry, 291 (30), 15674-15686. https://doi.org/10.1074/jbc.m116.727826
The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z α1-AT and why 15% of the expressed Z α1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in α1-AT. The results reveal that Z α1-AT has a labile strand 5 of the central β-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central β-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z α1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central β-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z α1-AT deficiency.
Humans, alpha 1-Antitrypsin Deficiency, alpha 1-Antitrypsin, Crystallography, X-Ray, Amino Acid Substitution, Protein Structure, Secondary, Mutation, Missense, Protein Stability
Wellcome Trust (082961/Z/07/Z)
British Heart Foundation (PG/09/072/27945)
External DOI: https://doi.org/10.1074/jbc.m116.727826
This record's URL: https://www.repository.cam.ac.uk/handle/1810/302066
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/