How Do Cytoskeletal Motor Proteins Work? A New Look Under The Hood of the Kinesin Molecular Machine

Kinesin molecular motors use energy derived from ATP to step along microtubules, driving many essential processes in eukaryotic cells including mitosis, vesicle transport and cytoskeletal remodeling. However, kinesin’s functional cycle, which occurs while the motor is attached to the microtubule, has not been characterized at atomic resolution. Thus, the detailed basis of motility has remained unclear. We used recent improvements in cryo-electron microscopy methodology and instrumentation to obtain 5-6Å resolution maps that capture the detailed conformation of a single kinesin motor domain at key points in the force-generation process. I will discuss how these results have allowed us to generate atomic-level models that can explain many key functional features of this beautiful molecular machine. I will also describe a recent breakthrough in our lab that allows us for the first time to study the detailed structure of kinesin “walkers”, in which pairs of co-assembled kinesin motor domains flip each other forward in a coordinated fashion to achieve continuous movement along the microtubule.