A decades-long mystery surrounding one of the nervous system’s most important molecular machines has been solved, providing a structural blueprint that could accelerate the development of targeted therapies for several inherited neurodegenerative diseases.
In a study published in Science Advances, researchers at the University of California, Davis report the first complete structure of kinesin-1—a motor protein that transports neurotransmitters, proteins, and other essential cargo throughout nerve cells—in its inactive state. The findings reveal how the protein is switched off until needed and identify structural features that could serve as targets for future drugs.
Although kinesin-1 was the first member of the kinesin superfamily to be discovered and has been studied for more than 40 years, scientists have never fully understood how cells regulate its activity. The new study provides what the authors call “a structural answer,” revealing how motor activity and cargo binding are coordinated.
Kinesin-1 is essential for healthy neurons. The protein walks along microtubules using energy from ATP, carrying cargo from the cell body to distant parts of nerve cells. When this transport system fails, neurons cannot deliver the materials needed to function and survive, contributing to diseases including amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease type 2, and hereditary spastic paraplegia.
Using cryo-electron microscopy, the researchers captured the complete structure of kinesin-1 in its autoinhibited, or “off” state. They discovered that the protein folds into a compact configuration that simultaneously prevents the motor from moving and blocks cargo from attaching.
“This dual-inhibited kinesin architecture provides a comprehensive blueprint” for how the protein maintains its inactive state, the authors write. The structure also reveals distinct regulatory sites that can be unlocked to restore both movement and cargo transport.
The team also uncovered how the protein is activated. They propose that the microtubule-associated protein MAP7 binds kinesin-1 and triggers a series of structural changes that unfold the protein, releasing the motor domains and exposing the cargo-binding site. Once activated, kinesin can resume transporting essential cellular components through the neuron.
The findings have important implications for drug development because many disease-causing mutations disrupt kinesin-1’s ability to switch between its inactive and active states. Until now, researchers lacked the structural information needed to understand exactly how these mutations impair the protein or how they might be corrected.
With the complete structure now available, investigators can examine how specific mutations alter kinesin-1 and begin designing molecules that restore its normal function. Rather than replacing the defective protein, future therapies could stabilize its structure or correct the molecular interactions that prevent it from turning on.
The authors hope this discovery will aid in designing a molecule that would bind the mutant protein and correct its defect. They believe the study establishes “a clear foundation for future mutational studies” and provides “a powerful framework” for understanding how kinesin proteins are regulated across the broader superfamily.
While additional research is needed before therapies reach the clinic, the work provides the detailed structural roadmap that has long been missing. By revealing exactly how kinesin-1 is locked into its inactive state and how that lock can be released, the study identifies promising new targets for precision medicines aimed at restoring intracellular transport in neurodegenerative disease.
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