How the proteasome works: resolving a critical new level of regulation

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Proteasomes are essential cell regulators in all eukaryotes. They are involved in the turnover of most proteins by breaking down proteins that are old, damaged, or no longer needed. They also perform the highly regulated removal of specific proteins that signal to important and diverse events such as cell division, stress responses and chromatin maintenance. Despite 30 years of research, many of the fundamental aspects of proteasome function are still not fully characterised. We recently discovered an unexpected new level of proteasome regulation by divalent cations that challenges our current understanding of how the proteasome works. I want to build on our new data to unambiguously describe how proteasomes work inside the cells. For this I will use electron microscopy based structural analysis, together with biochemical and biophysical methods, to visualise in detail how they are regulated by divalent cations and how they recognise and process the proteins to be degraded. Because the proteasome is a critical cell regulator, understanding its fundamental working mechanisms will have a broad impact in biological sciences in general. The outputs of the proposed work have the potential of contributing to the clarification of critical mechanisms underlying conditions such as cancer progression, neurodegeneration, and aging, where proteasome dysfunction and calcium deregulation have been implicated, with impact for a wide range of beneficiaries. The proteasome is a well-established drug target for conditions including cancer, so in addition to improving basic knowledge the proposal has the potential to contribute to further developments in drug discovery and development.