New structure reveals how dynein motor domains interact and how a pair of cargo adaptors use conserved sequence motifs to scaffold the motor protein complex
To transport cargos along cytoskeletal filaments, cells rely on motor proteins. Dynein, a large motor protein complex, travels on microtubules and is responsible for transporting numerous cargos. To activate for transport, dynein binds its cofactor dynactin and an adaptor which attaches the complex to cargos. Understanding precisely how these cargo adaptors recruit dynein-dynactin, and how the resulting complex moves has so far been limited by a lack of high-resolution structural information. Now Sami Chaaban and Andrew Carter, in the LMB’s Structural Studies Division, have used electron cryo-microscopy (cryo-EM) to solve the structure of the complex bound to microtubules.
The resulting structure shows how dynein’s motor domains interact with each other and how a pair of cargo adaptors use conserved sequence motifs to scaffold the complex. These results help illustrate dynein’s stepping behaviour and how it attaches to its cargos.
To achieve this, the pair had to develop a technique to overcome the challenges of using cryo-EM to visualise proteins that sparsely decorate filaments. Sami, a member of Andrew’s group, locked the dynein-dynactin complexes in a state which tightly binds microtubules and isolates them from unbound complexes for cryo-EM visualization. In order to overcome the microtubules’ dominant signal, Sami solved the structures of the microtubules and computationally subtracted them from the micrographs. Single particle analysis techniques allowed the pair to then solve the structure of the dynein-dynactin complexes. This method has the potential to be applied to other difficult complexes decorating filaments.
This structure offers greater insights into the behaviour of dynein, an important breakthrough given its myriad roles in cells and frequent hijacking by viruses that enter our cells. Furthermore, mutations affecting dynein and its cofactors have been implicated in various diseases, including development neuropathies. Enhanced understanding of the dynein machinery is therefore an important step towards understanding how these diseases develop.
This work was funded by UKRI MRC, Wellcome and EMBO.
Structure of dynein-dynactin on microtubules shows tandem adaptor binding. Chaaban, S., Carter, AP. Nature
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