Real-Time Imaging Reveals How Lis1 Activates Dynein in Cells

Cells depend on intricate transport systems made up of microtubule highways and motor proteins to move vital materials, position organelles, and remove waste. Among these motor proteins, dynein plays a key role by transporting cargo toward the cell center. Dysfunction in dynein or its partner protein Lis1 can result in severe neurological disorders such as lissencephaly, a fatal birth defect. Understanding how dynein and Lis1 interact is crucial for developing therapies to address these conditions. 

Researchers from the Salk Institute and UC San Diego have advanced this understanding by creating short movies that capture Lis1 “turning on” dynein. These movies allowed the team to identify 16 distinct shapes formed by the proteins during their interaction, including several never seen before. This detailed visualization highlights potential sites for therapeutic intervention. The findings were published in Nature Structural & Molecular Biology.

Dynein consists of two identical halves, each with a stalk (attaching to microtubules), a tail (attaching to cargo), and a motor (powered by ATP). When inactive, dynein adopts a locked “Phi” state, detaching from microtubules. Lis1 acts as a key, unlocking dynein into an active “Chi” state, but previous insights were limited to static images.

Using a yeast model, the researchers slowed dynein activity and used time-resolved cryogenic electron microscopy to capture a 3D movie of dynein and Lis1 interacting. They observed that Lis1 first attaches to dynein’s motor, unlocking it and increasing ATP utilization. A second Lis1 attachment to the stalk completes the activation, fully enabling dynein’s function.

“These findings certainly take us closer than we’ve ever been to understanding why Lis1 dysfunction has such a devastating effect on dynein activity, and how that contributes to developmental and neurological disorders down the line,” says first author Agnieszka Kendrick.