Single-molecule characterization of cytoplasmic dynein

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DESCRIPTION (provided by applicant): Cytoplasmic dynein is a molecular motor crucially involved in many processes essential for correct neurological function. Its improper function causes failed neurodevelopment (e.g. Miller- Dieker Lissencephaly), neurodegeneration, and other cognitive diseases such as schizophrenia. The wide range of dynein roles is made possible by tuning its function with accessory proteins such as Lis1, NudE, and NudEL. However, while genetic studies, both via mutagenesis in model organisms, and via identification of causative/risk factors in human disease, have repeatedly established that these proteins are in the dynein pathway and are important for dynein function-that is, dynein-mediated transport is impaired when their function is lost-mechanistically it has been impossible to determine what they do, or why they are important. Lacking such knowledge makes understanding disease progression difficult, as well as making it impossible to rationally design therapeutic approaches to correct the impairments. Our work determines at a mechanistic level exactly how the different cofactors alter dynein function, and starts to determine the ways that these co-factors effects on dynein are themselves regulated. At a mechanistic level, we will better understand how dynein is turned off by NudE, and then re-activated by Lis1. At a global level, we will determine functionally what NudEL does to dynein function (if anything), and how the function of NudE, NudEL, and Lis1 are altered by phosphorylation. Since dynein is crucial for many aspects of neuronal function, this will importantly advance the general field of neurobiology, and possibly allow design of more targeted therapeutic approaches.