Journal Article

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

Huntington, James A., Li, Wei, Yamasaki, Masayuki, Johnson, Daniel J. D.

2008

Overview

The molecular basis of serpin polymerization The serpins are a family of proteins that can multimerize via β-sheet linkages. Accumulation of such multimers can give rise to diseases such as thrombosis, cirrhosis and dementia. While the structures of many serpins are known, the structure of the linkage between monomers was unclear. In this work, Huntington and colleagues have solved the crystal structure of an antithrombin dimer. They find that the high stability of the serpin polymer is due to a large domain swap between beta sheets of the neighbouring monomers. In addition, the structure explains the how certain pathogenic mutations stabilize a polymerogenic folding intermediate. 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 encephalopathies 1 . A family of proteins, known as the serpins, also forms large stable multimers by ordered β-sheet linkages leading to intracellular accretion and disease 2 . These ‘serpinopathies’ include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in α 1 -antitrypsin (α 1 AT), and thrombosis caused by mutations in antithrombin 3 . 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 diseases 4 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Accretion / Analytical, structural and metabolic biochemistry / Antithrombin III - chemistry / Antithrombin III - metabolism / Biological and medical sciences / Biopolymers - chemistry / Biopolymers - metabolism / Crystallography / Crystallography, X-Ray / Dementia disorders / Dimerization / Enzymes and enzyme inhibitors / Fundamental and applied biological sciences. Psychology / Humanities and Social Sciences / Humans / Hydrolases / letter / Models, Molecular / multidisciplinary / Mutation / Nerve proteins / Physiological aspects / Plasma / Polymerization / Polymers / Protein Conformation / Proteins / Science / Science (multidisciplinary) / Thromboembolism