Structural Basis of Serpin Polymerisation

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Many of the most prominent diseases of our age are cause by the self-association of proteins. These include Alzheimer?s, Huntington?s, Parkinson?s Diseases and the prion encephalopathies, such as Mad-Cow Disease, Scrapie and Creutzfeldt-Jakob Disease. These disorders have been classified as conformational diseases because the underlying protein alters its conformation to deposit stable aggregates either within or outside of cells. A family of proteins called the serpins can also self-associate to create stable intercellular deposits, through a mechanism called polymerisation, leading to dementia, cirrhosis and thrombosis, among other diseases. It is generally accepted that the design of successful treatment for any of the conformational diseases will require a detailed understanding of the conformational changes that lead to self-association. In this grant we investigate how serpins polymerise by using a combination of biochemical and structural techniques. We have recently solved a structure of a stable serpin dimer that revealed an unexpected, large-scale linkage and explained the infectivity of polymers and suggested how monomers become polymerogenic. We will determine if this mechanism underlies polymerisation of serpins in general and inside of living cells. The result will be a molecular picture of the monomeric and polymeric species to allow the rational design of drugs to slow, prevent or even reverse pathogenic protein association.