Abstract
Molecular motors such as kinesin-1 drive active, long-range transport of cargos along microtubules in cells. Thermal diffusion of the cargo can impose a randomly directed, fluctuating mechanical load on the motor carrying the cargo. Recent experiments highlighted a strong asymmetry in the sensitivity of single-kinesin run length to load direction, raising the intriguing possibility that cargo diffusion may non-trivially influence motor run length. To test this possibility, here we employed Monte Carlo-based simulations to evaluate the transport of cargo by a single kinesin. Our simulations included physiologically relevant viscous drag on the cargo and interrogated a large parameter space of cytoplasmic viscosities, cargo sizes, and motor velocities that captures their respective ranges in living cells. We found that cargo diffusion significantly shortens single-kinesin runs. This diffusion-based shortening is countered by viscous drag, leading to an unexpected, non-monotonic variation in run length as viscous drag increases. To our knowledge, this is the first identification of a significant effect of cargo diffusion on motor-based transport. Our study highlights the importance of cargo diffusion and load-detachment kinetics on single-motor functions under physiologically relevant conditions.
Highlights
Molecular motors such as kinesin-1 drive active, long-range transport of cargos along microtubules in cells
Our simulations revealed that cargo diffusion significantly shortens single-kinesin run length at low viscous drag; this diffusion-based shortening effect arises from the specific asymmetry in the response of kinesin run length to load direction
The effect of load on run length is modeled by the motor’s load-detachment kinetics (Methods), which describes the probability of the motor detaching from the microtubule per unit time (“detachment rate”) for a given load value and direction
Summary
Molecular motors such as kinesin-1 drive active, long-range transport of cargos along microtubules in cells. Our study highlights the importance of cargo diffusion and load-detachment kinetics on single-motor functions under physiologically relevant conditions Molecular motors such as kinesin-1 are mechanoenzymes that drive long-range transport of cargos in living cells[1,2]. Kinesin-1 was thought to be affected by load oriented in the direction opposite (“hindering”) of motor motion, but not by load oriented in the same (“assisting”) direction This notion was reflected in previous numerical modeling studies, including work that predicted a null effect of cargo diffusion on single-kinesin transport[9]. Our simulations revealed that cargo diffusion significantly shortens single-kinesin run length at low viscous drag; this diffusion-based shortening effect arises from the specific asymmetry in the response of kinesin run length to load direction
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