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DYNEINOME Report Summary

Project ID: 338410
Funded under: FP7-IDEAS-ERC
Country: Portugal

Mid-Term Report Summary - DYNEINOME (Cytoplasmic Dynein: Mechanisms of Regulation and Novel Interactors)

Cytoplasmic dynein 1, a large multi-protein complex, is the predominant microtubule minus-end-directed motor in animals. Dynein participates in a wide range of cellular activities, ranging from the transport of proteins, RNA, and vesicles to nuclear migration and cell division. This ERC project investigates the regulatory mechanisms that give rise to dynein's functional diversity. We use live-cell fluorescence microscopy, genetics, and biochemical approaches in the roundworm Caenorhabditis elegans to study the roles and molecular mechanisms of co-factors and adaptors that associate with dynein to modulate localization, interaction with cargo, and motor activity. Although we know the identity of several dynein co-factors and cargo adaptors, in no context do we have a clear molecular understanding of how dynein is recruited and locally activated. Our work provides the most detailed view to date of how dynein is targeted to a subcellular structure, the mitotic kinetochore. Dynein was the first microtubule-binding protein identified at kinetochores, with two key functions in chromosome segregation: 1) dynein facilitates the capture of microtubules, accelerating the formation of stable kinetochore-microtubule attachments, and 2) dynein controls spindle assembly checkpoint (SAC) signaling by transporting SAC components away from attached kinetochores. Previous work had identified a requirement for the three-subunit Rod/Zw10/Zwilch complex (RZZ) and the coiled-coil adapter Spindly in dynein recruitment to kinetochores, but the molecular mechanism remains unknown. We have defined the protein-protein interactions that link RZZ to Spindly and Spindly to dynein and its co-factor dynactin, and demonstrated the functional relevance of these interactions both biochemically and in vivo. Furthermore, we show that the mechanism that is used by the kinetochore to engage dynein is also relevant for how dynein interacts with cargo adapters in the context of intracellular transport.

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