Kinesin-3 Motors are Marathon Runners of the Cellular World

In eukaryotic cells, long-distance intracellular transport relies on molecular motor proteins (kinesins and dyneins) that convert the chemical energy of ATP hydrolysis into mechanical energy for force generation and motility along microtubule tracks.  In mammals, kinesins constitute a large superfamily of proteins that are grouped into 14 families (kinesin-1 through kinesin-14).  The kinesin-3 family is one of the largest families of kinesin motors and consists of five subfamilies and play important roles in a wide range of cellular transport activities. Defects in kinesin-3 transport have been implicated in a variety of genetic, developmental, and neurodegenerative diseases and cancer, yet the molecular mechanisms of kinesin-3 regulation and cargo transport are largely unknown.  We performed a comprehensive analysis of mammalian kinesin-3 motors and find that kinesin-3 motors employ a unique mechanism of regulation in which non-cargo-bound motors are monomeric and inactive whereas cargo-bound motors are dimeric and processive.  The molecular mechanisms that regulate the monomer-to-dimer transition center around the neck coil (NC) segment and its ability to undergo intramolecular interactions in the monomer state versus intermolecular interactions in the dimer state.  In the case of KIF13A and KIF13B, we suggest that dimerization requires the release of a proline-induced turn between the NC and subsequent CC1 segments.  We show that dimerization of kinesin-3 motors results in inherently fast and remarkably superprocessive motility, with average run-lengths of ~ 10 mm.  Such high processivity has not been observed for any other motor protein and suggests that kinesin-3 motors are evolutionarily adapted to serve as the marathon runners of the cellular world.Thekinesin-3 family members are the major kinesins in neurons, my future work will continue to investigate kinesin-3 motors to gain fundamental insights into how the structural and mechanochemical features of kinesin-3 motors relate to their neuronal transport and functions and how defects in cargo transport play a causal role in neurodegenerative, developmental, and cancer diseases in higher organisms.  This will in turn aid in development of new drugs and therapies to cure these diseases.