KIF1A kinesin motor proteins transport cargo anterogradely along microtubules in the axons of neurons.

KIF1A kinesin motor proteins transport cargo anterogradely along microtubules in the axons of neurons.

Recently, Lessard et al. investigated how polyglutamylation of tubulin’s C-terminal tails (CTTs) regulates processivity of the neuron-specific kinesin motor KIF1A. KIF1A transports neuronal cargo anterogradely along axonal microtubules (MTs) over long distances (~3 microns). Prior studies implicated interactions between the K-loop of KIF1A and polyglutamylated CTTs in the regulation of KIF1A motility. The K-loop is a lysine-rich surface loop that attaches the motor to MTs via interactions with glutamate-enriched tubulin CTTs. Single-molecule total internal reflection fluorescence microscopy was utilized to better understand how polyglutamylation regulates KIF1A motility. Dimeric KIF1A exhibited novel, stochastic pausing behavior during motility on paclitaxel-stabilized MTs.  Such pauses enabled KIF1A to combine multiple sequential runs into a super-processive run length. Furthermore, the K-loop/CTT interaction positively regulated KIF1A’s landing rates onto MTs and pause frequency and duration. Moreover, CTT polyglutamylation regulated this interaction and KIF1A’s subsequent motile behavior. Cytoskeleton’s 99% pure rhodamine-labeled porcine brain tubulin (Cat.# TL590M) was essential as the motor substrate for TIRF microscopic analyses of how K-loop/CTT interactions regulate KIF1A’s processivity. These results provide novel mechanistic insights into KIF1A-mediated axonal transport and the regulatory role of tubulin CTT polyglutamylation, which may further clarify how dysfunctional MT-based, kinesin-mediated axonal transport contributes to neurodegeneration.

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Ryan Kogstad