Abstract
Kinesin-3 motors drive the transport of synaptic vesicles and other membrane-bound organelles in neuronal cells. In the absence of cargo, kinesin motors are kept inactive to prevent motility and ATP hydrolysis. Current models state that the Kinesin-3 motor KIF1A is monomeric in the inactive state and that activation results from concentration-driven dimerization on the cargo membrane. To test this model, we have examined the activity and dimerization state of KIF1A. Unexpectedly, we found that both native and expressed proteins are dimeric in the inactive state. Thus, KIF1A motors are not activated by cargo-induced dimerization. Rather, we show that KIF1A motors are autoinhibited by two distinct inhibitory mechanisms, suggesting a simple model for activation of dimeric KIF1A motors by cargo binding. Successive truncations result in monomeric and dimeric motors that can undergo one-dimensional diffusion along the microtubule lattice. However, only dimeric motors undergo ATP-dependent processive motility. Thus, KIF1A may be uniquely suited to use both diffuse and processive motility to drive long-distance transport in neuronal cells.
Highlights
Kinesin motors drive the long-distance transport of membrane-bound cargoes along microtubules
Motor activity must be tightly regulated to ensure that ATP hydrolysis and processive motility occur only upon coupling to the correct cargo
Kinesin-3 motors drive the transport of presynaptic vesicles and other membrane-bound organelles along microtubule tracks
Summary
Kinesin motors drive the long-distance transport of membrane-bound cargoes along microtubules. Transport of synaptic vesicle precursors to axon terminals is driven by members of the Kinesin-3 family, the mammalian KIF1A, and Caenorhabditis elegans Unc104 motors [1]. Autoinhibition typically involves a folded state that enables the motor’s own tail domain to interact with and inhibit its motor domain. This model is based on a large body of work on the Kinesin-1 motor (formerly conventional kinesin or KIF5) [2,3,4,5]. Autoinhibition may be a general model for motor regulation, as two well-studied members of the myosin family, nonmuscle myosin II and myosin V, exist in a folded inactive state [9,10,11]. Autoinhibition enables precise spatial and temporal regulation of motors and may be relieved by cargo binding [6,12], phosphorylation [8], or other mechanisms
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