Kinesin-3 Motors are Marathon Runners of the Cellular World

Abstract:In eukaryotic cells, long-distance intracellular transport relies on molecular motor proteins (kinesin and dynein) 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 functions. Defects in kinesin-3 transport have been implicated in a variety of genetic, developmental, neurodegenerative and cancer diseases. Despite their wide spread function and clinical significance, 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 monomeric motors undergo cargo-mediated dimerization to result processive motion critical for cargo transport. The molecular mechanisms that regulate the monomer-to-dimer transition center around the neck coil (NC) segment. Surprisingly, we show for the first time 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 critical for long-distance neuronal transport. Intriguingly, my previous work determining the mechanism of reversals during bidirectional cargo transport has elegantly demonstrated how mechanochemical properties of kinesin and dynein motors relate to their ensemble functions on cellular cargo critical for bidirectional transport, receptor recycling and endosome maturation. As kinesin-3 family members are the major kinesins in neurons, my future work, therefore, 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.