RT Journal Article
SR Electronic
T1 Conformational transitions of the mitotic adaptor Spindly underlie its interaction with Dynein and Dynactin
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.02.478874
DO 10.1101/2022.02.02.478874
A1 Ennio d’Amico
A1 Misbha Ud Din Ahmad
A1 Verena Cmentowski
A1 Mathias Girbig
A1 Franziska Müller
A1 Sabine Wohlgemuth
A1 Andreas Brockmeyer
A1 Stefano Maffini
A1 Petra Janning
A1 Ingrid R. Vetter
A1 Andrew P. Carter
A1 Anastassis Perrakis
A1 Andrea Musacchio
YR 2022
UL http://biorxiv.org/content/early/2022/02/02/2022.02.02.478874.abstract
AB Cytoplasmic Dynein 1, or Dynein, is a microtubule minus-end directed motor. Dynein 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. How activating adaptors limit Dynein activation to specialized subcellular locales is unclear. Here, we reveal 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 mechanism may be paradigmatic for Dynein activation by other adaptors at various cellular locales.Competing Interest StatementThe authors have declared no competing interest.