Dynamical Effects of KIF1A Mutations in Neurodevelopmental Disorders

Abstract

KIF1A is a molecular motor of the kinesin-3 family of motor proteins, with primary function of anterograde transport of synaptic vesicle precursors along axonal microtubules. Recently, a number of disease-associated genetic variants and de novo mutations have been identified from clinical studies. These mutations have been linked to neurodevelopmental disorders including cognitive disability, spasticity, and cerebellar and optic nerve atrophy. The mechanism of how these mutations disrupt motor function is not understood. We used molecular dynamics simulations to characterize dynamical effects of mutations localized to the motor domain of KIF1A. We focused on the V8M mutation, which is localized on the first beta strand (β1), and hypothesized that this V8M would decrease the force generation of KIF1A. We observed significant changes in residue-residue interactions for three functionally important domains. First, V8M impacted residues involved the power stroke i.e., neck linker (NL), cover strand (CS), β7, L13, and suggest an unexpected output of enhanced NL docking. Second, differences in interactions between nucleotide coordinating residues in a0, P loop, L9/switch-1, L11/switch-2, indicate an impact on ATPase activity. Third, decreased interactions for residues interacting with the microtubule in a4, L11/switch-2, L13, a6 suggest the V8M motor is slower and less processive, consistent with previous experimental work (Scarabelli et al 2015). Current efforts are focused on experimentally measuring the kinetic and motility properties of mutant motors. Our results demonstrate the allosteric effects of KIF1A neurological disease-associated mutations and help us better understand how mutations in kinesin motors can lead to neurodevelopmental disorders.