Kinesin-1 is a motor protein responsible for transporting cargoes such as vesicles, RNA or protein complexes, and organelles across large distances in the cell. Kinesin-1 transports these cargoes by stepping along microtubule tracks through ATP-coupled alternating attachment and detachment of its two motor domain heads. This stepping is highly processive, and occurs via an asymmetric hand-over-hand mechanism, in which the two heads take alternating left and right steps1. The fact that the two steps are different indicates that the kinesin homodimer can have two different structures in even and odd steps, but how this happens in a dimer with two identical subunits is unclear. One known contributor to processivity and hypothesized contributor to asymmetry is the dimerization domain between the two heads, termed the neck coiled-coil. The neck coiledcoil lays down tangent to the microtubule2, and most likely increases processivity by providing an additional kinesin binding platform through electrostatic interactions with the microtubule surface3. It is plausible that the neck coiled-coil/microtubule interaction causes the structural differences between steps that lead to asymmetry. Here, I will use single molecule methods to investigate the structure of the neck coiled-coil during stepping, and define how the interactions between the neck coiled-coil and the microtubule affect kinesin structure and asymmetric stepping. These studies will add new insight into how the structure of the kinesin neck-coiled coil influences both processivity and asymmetric stepping, aspects of the kinesin mechanism that enable it to undergo long distance transport in vivo.
Defects in kinesin-1 transport have been shown to contribute to neurological diseases such as Alzheimer's4;5, Huntington's6, Amyotrophic Lateral Sclerosis (ALS)7, and Fragile-X syndrome8. Understanding the mechanism of kinesin-1 transport will contribute to our understanding of the molecular bases of these diseases.