Citation Spotlight: Polyglutamylation Regulates Motility of Neuron-specific KIF1A Kinesin

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

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