Some bacteria build sticky amyloid fibres on purpose, using them to form protective biofilms that help them survive hostile environments and cause infections. This matters because the same type of protein aggregation that bacteria control so precisely goes disastrously wrong in human diseases like Alzheimer’s and Parkinson’s. While scientists understand the toxic end result in humans, they know very little about how microbes safely assemble these fibres without killing their own cells. The researchers aim to map the molecular machinery that transports amyloid subunits across membranes and assembles them into functional structures. If successful, this fundamental science project will provide the first detailed atomic picture of a controlled amyloid assembly line. That knowledge could eventually suggest ways to disrupt bacterial biofilms that clog medical implants or resist antibiotics. It might also reveal why human cells lose control of similar proteins—offering clues for future therapies against neurodegenerative diseases. The team is developing new nuclear magnetic resonance methods to study large protein complexes, which could benefit structural biology more broadly.
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In contrast to human disease-associated amyloidogenesis that underlie neurodegenerative disorders like Alzheimers and Parkinsons disease, many microbial organisms possess elaborate molecular machineries that facilitate the assembly of amyloid fibres in a highly regulated, non-cytotoxic manner. The resulting polymeric structures are multifunctional, often enabling biofilm formation in extreme environments, modulating host cell adhesion and contributing to pathogenicity during infection. We aim to unravel the molecular processes that control the assembly of functional amyloids and biofilm formation, which may also offer clues to controlling pathogenic amyloids in humans. Crucial to our understanding is a deep atomic and mechanistic knowledge of how amyloid subunits are safely transported across membranes and between cellular compartments. Although the amenability of microbial systems to manipulation and functional readouts means they are important model systems, there have been rela tively few in-depth studies on the pathways of amyloidogenesis control. Our approach engages multi-disciplinary and complementary methods that aim to marry biological insight with quantitative data. In addition to employing a diverse array of molecular and high resolution structural tools, we are developing new nuclear magnetic resonance methods to assist in mapping structural, dynamic and interactional changes in large protein assemblies, including membrane proteins. Studying key molecular p rocesses used by pathogenic microorganisms not only provides insights into disease pathways, it often illuminates fundamental cell biology in higher eukaryotes and will provide a foundation for future translational activities.
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