Modeling the motion of disease-associated KIF1A heterodimers

Abstract

KIF1A is a member of the kinesin-3 motor protein family that transports synaptic vesicle precursors in axons. Mutations in the Kif1a gene cause neuronal diseases. Most patients are heterozygous and have both mutated and intact KIF1A alleles, suggesting that heterodimers composed of wild-type KIF1A and mutant KIF1A are likely involved in pathogenesis. In this study, we propose mathematical models to describe the motility of KIF1A heterodimers composed of wild-type KIF1A and mutant KIF1A. Our models precisely describe run length, run time, and velocity of KIF1A heterodimers using a few parameters obtained from two homodimers. The first model is a simple hand-over-hand model in which stepping and detachment rates from a microtubule of each head are identical to those in the respective homodimers. Although the velocities of heterodimers expected from this model were in good agreement with the experimental results, this model underestimated the run lengths and run times of some heterodimeric motors. To address this discrepancy, we propose the tethered-head affinity model, in which we hypothesize a tethered head, in addition to a microtubule-binding head, contributes to microtubule binding in a vulnerable one-head-bound state. The run lengths and run times of the KIF1A heterodimers predicted by the tethered-head affinity model matched well with experimental results, suggesting a possibility that the tethered head affects the microtubule binding of KIF1A. Our models provide insights into how each head contributes to the processive movement of KIF1A and can be used to estimate motile parameters of KIF1A heterodimers.