Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Wednesday Speaker Abstracts

FORCE GENERATION BY THE KINESIN-3 FAMILY MOTOR PROTEIN KIF1A AND ITS DISRUPTION IN KIF1A-ASSOCIATED NEUROLOGICAL DISORDER Kumiko Hayashi The University of Tokyo, The Institute for Solid State Physics, Kashiwa, Japan KIF1A is a member of the kinesin-3 family of ATP-dependent microtubule motor proteins that functions as a dimer and drives anterograde transport of synaptic vesicle precursors and other cargos along axonal and dendritic microtubules. Pathogenic variants in KIF1A cause a neurodegenerative disorder known as KIF1A-associated neurological disorder (KAND), which exhibits substantial allelic heterogeneity and a broad spectrum of clinical manifestations, including seizures, cognitive impairment, optic nerve atrophy, spasticity, and peripheral neuropathy. Recent studies have begun to establish clinical severity scores for KAND and to link clinical phenotypes with the genotype and molecular properties of the KIF1A motor. Disease severity has been shown to be strongly associated with variants located in protein regions involved in ATP and microtubule binding, including the P loop, switch I, and switch II. For such variants, recombinant KIF1A proteins were generated to investigate microtubule binding, motor velocity, and processivity. In this study, we investigated KAND from a biophysical perspective by focusing on stall force as a key physical parameter of motor function. Using DNA origami technology, we developed a nanospring, a fluorescently visible molecular spring that quantifies force through its extension. Unlike kinesin-1, KIF1A readily detaches from microtubules under perpendicular loads typically applied in optical tweezers experiments, making accurate stall force measurements particularly challenging. By applying force parallel to the microtubule using the nanospring, we precisely quantified the stall force of KAND-associated mutants. We further examined the relationship between stall force and clinical severity scores in KAND, thereby linking motor-level force generation to disease severity.

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