Unbinding of Kinesin from Microtubule in the Strongly Bound States Enhances under Assisting Forces

Abstract

The ability to predict the cellular dynamics of intracellular transport has enormous potential to impact human health. A key transporter is kinesin-1, an ATP-driven molecular motor that shuttles cellular cargos along microtubules (MTs). The dynamics of kinesins depends critically on their unbinding rate from MT, which varies depending on the force direction applied on the motor, i.e. the force-unbinding rate relation is asymmetric. However, it remains unclear how changing the force direction from resisting (applied against the motion direction) to assisting (applied in the motion direction) alters the kinesin's unbinding and stepping. Here, we propose a theoretical model for the influence of the force direction on the stepping dynamics of a single kinesin. The model shows that the asymmetry of the force-unbinding rate relation is independent of ATP concentration. It also reveals that the synthesis of ATP from backward stepping under assisting forces is less likely than under resisting forces. It then finds that the unbinding of kinesin in the strongly MT-bound kinetic states enhances under assisting forces.

Processivity of molecular motors under vectorial loads

“…Future work can also consider the effects of the backward stepping (velocity) of the motor on its processivity, upon the availability of the velocity and detachment rate data over high resisting and assisting loads. Backward steps of kinesin, on average, are driven by ATP hydrolysis at force above the stalling conditions [10,[41][42][43][44], although ATP synthesis can result in backward stepping [19,20]. It is interesting to study the effect of the ATP concentration on the processivity.…”

Crowding and Pausing Strongly Affect Dynamics of Kinesin-1 Motors along Microtubules

“…The major drawback of our method is at once its greatest strength: our approach is very indirect. The application of forces to kinesin motors, e.g., by using optical traps (57, 61) as well as the attachment of large labels such as gold particles to kinesin heads (50, 62) might have crucial influence on motor dynamics (64). Therefore, indirect methods (63, 64, 65) such as the approach employed in this work are essential to confirm and improve experimental results found by direct observation.…”

Force Generated by Two Kinesin Motors Depends on the Load Direction and Intermolecular Coupling

“…[38] and used in Refs. [22,39,40], N is truncated when the occupancy probability of the most strained state falls below 1%, with a minimal effect on the calculations; see Fig. 3(b) and Ref.…”