Microscopic Movies Reveal Protein Interactions That May Unlock Treatments for Brain Disorders.

In a groundbreaking study, researchers from the Salk Institute and the University of California San Diego have created high-definition, time-resolved 3D movies showing how two crucial brain proteins interact in real time. The research, published on May 23, 2025, in Nature Structural & Molecular Biology, captures the activation process of dynein—a vital motor protein—by its regulatory partner Lis1, offering valuable new insight into cellular transport systems and the roots of certain neurological disorders.

Cells depend on internal "highways" known as microtubules, along which motor proteins like dynein carry out essential tasks, from relocating organelles to transporting genetic instructions and clearing cellular waste. Malfunctions in these proteins or their regulators can result in serious health issues. One such condition is lissencephaly, a fatal birth defect caused by mutations in the Lis1 protein, which is essential for activating dynein. Despite its severity, no effective treatments currently exist.

The team’s new research reveals how Lis1 physically interacts with dynein to unlock its functionality—an understanding that could be pivotal in designing drugs to correct such dysfunctions. By capturing the molecular interaction in motion rather than relying on static snapshots, the researchers identified 16 distinct structural shapes that dynein assumes while being activated by Lis1, several of which were previously undocumented.

“What makes dynein especially fascinating is its unique ability to move toward the center of the cell,” said Agnieszka Kendrick, co-corresponding author and assistant professor at the Salk Institute. “The advanced tools we now have enabled us to witness its interaction with Lis1 in real time, which provides a much clearer understanding of how to potentially restore their function in diseases.”

Dynein is composed of two symmetrical halves, each featuring a stalk (which attaches to the microtubule), a tail (which carries the cargo), and a motor (which powers its movement). Its motion resembles walking, as it consumes ATP—the cell's energy currency—to move step-by-step along microtubules. When idle, dynein adopts a tightly folded, inactive form called “Phi.” Previous studies had shown that Lis1 acts like a key, shifting dynein into an active, open shape known as “Chi.” However, these conclusions were based on isolated images of different stages in the interaction.

To deepen this understanding, the researchers used a yeast model system, which allows for survival even when dynein or Lis1 levels are modified. Importantly, dynein functions similarly in yeast and human cells, making the results highly applicable to human biology.

Using time-resolved cryogenic electron microscopy (cryo-EM), the team dramatically reduced the temperature to slow dynein’s activity, allowing them to record a high-resolution movie showing the full transition from Phi to Chi. Cryo-EM uses electron beams to construct atomic-level 3D images, and the time-resolved method captures these images at multiple moments, revealing changes over time rather than just static views.

The movie revealed that the activation of dynein begins when one half of the Lis1 protein binds to dynein’s motor region, unlocking its shape and boosting its ability to process ATP. This binding activates dynein’s movement. Then, the second half of Lis1 attaches to dynein’s stalk, fully stabilizing its active Chi state and enhancing its motor capabilities.

“Our approach gave us the most complete picture yet of how Lis1 activates dynein,” said co-author Andres Leschziner, professor at UC San Diego. “Several of the shapes we observed had never been seen before.”

These new insights provide a structural roadmap for drug development aimed at correcting protein dysfunctions that contribute to neurological diseases. Future work will explore how mutations in Lis1 affect its binding ability and influence disorders like lissencephaly.

“This takes us a significant step closer to understanding the molecular causes behind these devastating conditions,” Kendrick emphasized.

Other contributors to the study include Kendrick Nguyen, Eva Karasmanis, and Rommie Amaro of UC San Diego; Samara Reck-Peterson of UC San Diego and the Howard Hughes Medical Institute; and Wen Ma of the University of Vermont.

Source:https://phys.org/news/2025-05-microscopic-movies-capture-brain-proteins.html

This is non-financial/medical advice and made using AI so could be wrong.