Regulating amyloid formation: structural studies of the secretion and assembly of 'curli' fibres

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Proteins are important building blocks for cells and organs, as well being important messengers that circulate throughout an organism. Occasionally, cells produce abnormal proteins that have tendency to form fibrous protein aggregates. The mis-folding of proteins and their subsequent accumulation into what are now termed ?amyloids? has a major detrimental effect on the health of a cell. Amyloids are therefore implicated in the causes of numerous human diseases, such as type-2 diabetes mellitus, Alzheimer?s and Parkinson?s. Despite the damaging effects of amyloid deposits, bacteria have devised a way of carefully controlling their formation, such that they are prevented from damaging the cell. Bacteria also utilise these fibrous structures, known as ?curli?, to their advantage, such as promoting biofilms and shielding themselves from extreme environmental changes. The curli assembly and secretion system includes a membrane pore that transports amyloid subunits to the outside of the cell and a number of accessory/chaperone molecules that assist in regulating the process. We propose to study the structures and interactions of the curli assembly and secretion system with a view to understanding its mode of action in atomic detail. Current treatments for amyloid diseases of humans are limited and truly effective remedies have yet to be developed, therefore they represent a major public health concern. Our studies will provide guidance for the rational design of new therapeutic approaches for preventing or treating slowing amyloid diseases in humans.