Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization

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Repeating intermolecular protein association by means of β-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer’s, Huntington’s and Parkinson’s and the prion encephalopathies1. A family of proteins, known as the serpins, also forms large stable multimers by ordered β-sheet linkages leading to intracellular accretion and disease2. These ‘serpinopathies’ include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in α1-antitrypsin (α1AT), and thrombosis caused by mutations in antithrombin3. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the β-sheet expansion disorders collectively known as the conformational diseases4. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel β-strands inserting in the centre of the principal β-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible β-sheet expansion.

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Figure 1: Crystallographic structures of active, latent and self-terminating dimer of the serpin antithrombin.
Figure 2: Biochemical properties of serpin polymers and the M* state.
Figure 3: Models of the serpin polymer and the M* state.

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Protein Data Bank

Data deposits

Atomic coordinates and structure factors have been deposited in the Protein Data Bank under the accession code 2ZNH.


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We thank R. Carrell, D. Crowther and D. Lomas for their comments on the manuscript. We are also grateful to J. Löwe for access to the robotic crystallisation facility in the MRC-LMB, and to M. Weldon for N-terminal sequencing. This work was supported by the National Institutes of Health (USA) and the Uehara Memorial Foundation (Japan, to M.Y.), and J.A.H. is a senior MRC non-clinical fellow. Data were collected at beamlines I02 and I04 at the Diamond Light Source and we acknowledge the support of L. Duke, G. Evans, R. Flaig, J. Sandy and T. Sorensen.

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Correspondence to James A. Huntington.

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