Conformational transitions of the Spindly adaptor underlie its interaction with Dynein and Dynactin

d'Amico EA, Ud Din Ahmad M, Cmentowski V, Girbig M, Müller F, Wohlgemuth S, Brockmeyer A, Maffini S, Janning P, Vetter IR, Carter AP, Perrakis A. Musacchio A  (2020) Journal of Cell Biology


Dynein is a microtubule minus end-directed motor. Its motility requires Dynactin and a family of activating adaptors that stabilize the Dynein-Dynactin complex and promote regulated interactions with cargo in space and time.

Here the Musacchio lab reveals that Spindly, a mitotic Dynein adaptor at the kinetochore corona, exists natively in a closed conformation that occludes binding of Dynein-Dynactin to its CC1 box and Spindly motif. A structure-based analysis identified various mutations promoting an open conformation of Spindly that binds Dynein-Dynactin.

A region of Spindly downstream from the Spindly motif and not required for cargo binding faces the CC1 box and stabilizes the intramolecular closed conformation. This region is also required for robust kinetochore localization of Spindly, suggesting that kinetochores promote Spindly activation to recruit Dynein.
This work illustrates how specific Dynein activation at a defined cellular locale may require multiple factors.

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