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The structural basis for Z α1-antitrypsin polymerization in the liver
Sarah V Faull1, Emma L K Elliston1,2, Bibek Gooptu3,4,5
1UCL Respiratory, University College London, 5 University Street, London WC1E 6JF, UK.
Science Advances
|October 22, 2020
Summary
The study reveals that disease-associated alpha-1-antitrypsin (AAT) polymers in liver tissue share structural similarities with artificially induced polymers. This finding suggests a common mechanism involving a carboxyl-terminal domain swap in serpinopathies.
Area of Science:
- Biochemistry
- Structural Biology
- Pathology
Background:
- Serpinopathies are conformational diseases caused by protein misfolding and aggregation.
- Alpha-1-antitrypsin (AAT) deficiency is a key serpinopathy, characterized by mutant AAT polymers in liver tissue.
- The precise structure of these disease-associated polymers and their relation to artificial models are poorly understood.
Purpose of the Study:
- To structurally characterize polymers isolated from liver tissue of Z AAT homozygotes.
- To compare the structure of ex vivo polymers with heat-induced polymers.
- To elucidate the inter-subunit linkage in AAT polymers.
Main Methods:
- Isolation of polymers from liver explants of Z AAT homozygotes.
- Labeling of isolated polymers with a Fab fragment.
- Single-particle analysis of negative-stain electron micrographs.
Main Results:
- Structural equivalence was observed between heat-induced and ex vivo AAT polymers.
- The inter-subunit linkage in these polymers is best explained by a carboxyl-terminal domain swap.
- This structural insight provides a molecular basis for serpinopathy formation.
Conclusions:
- Disease-associated AAT polymers exhibit structural similarity to artificial models.
- A carboxyl-terminal domain swap is the likely mechanism for polymer formation in Z AAT deficiency.
- Understanding this mechanism is crucial for developing therapeutic strategies for serpinopathies.
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