Some of the most devastating diseases known to humanity, such as: Alzheimer’s, Parkinson’s, ALS, Multiple Sclerosis, and others, are neurodegenerative in nature. Pathogens attack neurons in various parts of the brain and central nervous system, thereby disrupting and destroying normal cognitive, memory, and nerve function.
A critically important area of frontier life science research involves understanding how neurons and their networks grow, adapt to influences, process electrical impulses from the brain across synapses to other cells, and throughout a neuron’s life, how it develops and maintains plasticity. Evidence has emerged that kinesin motor proteins play a crucial role in many of these functions.
Motor proteins, such as kinesin-1, are able to carry cargos, such as chromosomes, vesicles, and protein complexes, along cellular microtubules that act as ‘tracks’ for cells so that essential materials can be transported to parts of cells, an issue that is important regarding neurons as they can extend a considerable distance.
The success or failure of these motor proteins in carrying cargo is essential for many cellular functions, such as secretion, muscle contraction, cell division, and the positioning of organelles within cells. How kinesin-1 motor proteins execute their highly efficient, hand-over-hand style movement along microtubules is of great interest to scientists. Likewise, should kinesin-1 carry the wrong cargo, such as pathogens, for example, that can play a significant role in amplifying neurodegenerative disease.
Masahide Kikkawa and Michio Tomishige, both of The University of Tokyo and both recipients of a 2006 HFSP Research Grant – Early Career, published breakthrough research in the Journal of Cell Biology in July 2025 that explains a key mechanism governing kinesin-1 motor protein’s stepping movement. The paper, entitled “Tension-induced suppression of allosteric conformational changes coordinates kinesin-1 stepping,” is a direct result of the research grant.
Visualizations show kinesin-1 motor proteins exhibit a branched configuration with two ‘legs,’ also known as ‘neck linkers,’ that take turns stretching and planting one ‘foot,’ referred to as a ‘motor domain head,’ in front of the other to walk along a microtubule. With each step, the leading head binds to the microtubule, and an ATP hydrolysis reaction occurs. What scientists didn’t know was what prevented the trailing kinesin-1 head from prematurely binding to the microtubule while the partner head awaited ATP.
Effectively, the team wanted to understand what mechanism makes the kinesin-1 so efficient in its forward motion — not hurried, not uncoordinated — because processing ATP efficiently is as vital for successful life processes as getting the cargo to its destination.
Working across three laboratories in Japan, each employing different techniques, Kikkawa, Tomishige, and their colleagues utilized X-ray crystallography, cryo-electron microscopy, molecular dynamics simulations, and single-molecule fluorescence assays to investigate how the neck linkers move. While the trailing leg can stretch backward, to navigate forward, it must swing around a bulge located just ahead of the neck linker’s base, thus creating a bit of a swinging stride. The net effect introduces just enough tension into the coordinated movement to prevent premature binding of the tethered motor domain head.
Kikkawa, Tomishige, and their colleagues hypothesize that the tension-based mechanism may be crucial in preventing the trailing neck linker and head from rebinding to the rear binding site, and the coordinated stepping appears to also favor forward motion.
Additional studies are needed to examine whether this mechanism extends to other kinesin subfamilies with different neck linker properties, such as varying neck linker lengths (kinesin-2 and kinesin-3), and if there are unique interactions with kinesin-6.
Masahide Kikkawa served as Vice-Chair of the HFSP Council of Scientists from 2020 to 2024.
The co-authors were members of a 2006 HFSP Research Grant – Early Career project entitled, “Kinesin motors under load applied by ‘nano-springs.” Team members included:
Imre Derenyi, Department of Biological Physics, Eotvos University, Budapest, Hungary
Masahide Kikkawa, Department of Cell Biology and Anatomy, The University of Tokyo, Tokyo, Japan
Michio Tomishige, Department of Applied Physics, The University of Tokyo, Tokyo, Japan