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bioRxiv · 10.1101/2025.01.14.632505

A Two-Heads-Bound State Drives KIF1A Superprocessivity

Rao, L.·Wirth, J. O.·Matthias, J.·Gennerich, A.
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Abstract

KIF1A, a neuron-specific Kinesin-3 motor, is indispensable for long-distance axonal transport and nuclear migration, processes vital for neuronal function. Using MINFLUX tracking, we reveal that KIF1A predominantly adopts a two-heads-bound state, even under ATP-limiting conditions, challenging prior models proposing a one-head-bound rate-limiting step. This two-heads-bound conformation, stabilized by interactions between the positively charged K-loop and negatively charged tubulin tails, enhances microtubule affinity and minimizes detachment. The shorter neck linker facilitates inter-head tension, keeping the heads out of phase and enabling highly coordinated stepping. In contrast, Kinesin-1 (KIF5B) transitions to a one-head-bound state under similar conditions, limiting its processivity. Perturbing KIF1As mechanochemical cycle by prolonging its one-head-bound state significantly reduces processivity, underscoring the critical role of the two-heads-bound state in motility. These findings establish a mechanistic framework for understanding KIF1As adaptations for neuronal transport and dysfunction in neurological diseases.

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Rao, L., Wirth, J. O., Matthias, J., Gennerich, A.. 2025-01-18. A Two-Heads-Bound State Drives KIF1A Superprocessivity. https://doi.org/10.1101/2025.01.14.632505

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