2024 March 29; 383(6690): eadk8544. doi:10.1126/science.adk8544. | Kashish Singh#, Clinton K. Lau#1,3, Giulia Manigrasso1, José B. Gama2, Reto Gassmann2, Andrew P. Carter1,*
The study investigates the molecular mechanism of dynein-dynactin complex assembly, focusing on the role of LIS1 and the lysosomal adaptor JIP3. Using cryo-electron microscopy, the researchers determined the structure of the dynein-dynactin complex bound to JIP3 and LIS1 on microtubules. The structure reveals that JIP3 recruits two dynein dimers per dynactin, with LIS1 binding to the p150 subunit of dynactin, tethering it along the length of dynein. This interaction is crucial for efficient complex formation. The study also shows that JIP3 is autoinhibited by an intramolecular interaction between its JIP3helix and RH1 domains, which hinders dynein activation. Additionally, the structure suggests that LIS1 stabilizes the pre-powerstroke state of dynein-A, overriding the conformation dictated by the bound nucleotides. The findings provide insights into how dynein-dynactin complexes are assembled and activated, highlighting the critical role of LIS1 and the interaction between LIS1 and p150 in this process.The study investigates the molecular mechanism of dynein-dynactin complex assembly, focusing on the role of LIS1 and the lysosomal adaptor JIP3. Using cryo-electron microscopy, the researchers determined the structure of the dynein-dynactin complex bound to JIP3 and LIS1 on microtubules. The structure reveals that JIP3 recruits two dynein dimers per dynactin, with LIS1 binding to the p150 subunit of dynactin, tethering it along the length of dynein. This interaction is crucial for efficient complex formation. The study also shows that JIP3 is autoinhibited by an intramolecular interaction between its JIP3helix and RH1 domains, which hinders dynein activation. Additionally, the structure suggests that LIS1 stabilizes the pre-powerstroke state of dynein-A, overriding the conformation dictated by the bound nucleotides. The findings provide insights into how dynein-dynactin complexes are assembled and activated, highlighting the critical role of LIS1 and the interaction between LIS1 and p150 in this process.