Load‐dependent detachment kinetics plays a key role in bidirectional cargo transport by kinesin and dynein

Abstract

Bidirectional cargo transport along microtubules is carried out by opposing teams of kinesin and dynein motors. Despite considerable study, the factors that determine whether these competing teams achieve net anterograde or retrograde transport in cells remain unclear. The goal of this work is to use stochastic simulations of bidirectional transport to determine the motor properties that most strongly determine overall cargo velocity and directionality. Simulations were carried out based on published optical tweezer characterization of kinesin-1 and kinesin-2, and for available data for cytoplasmic dynein and the dynein-dynactin-BicD2 (DDB) complex. By varying dynein parameters and analyzing cargo trajectories, we find that net cargo transport is predicted to depend minimally on the dynein stall force, but strongly on dynein load-dependent detachment kinetics. In simulations, dynein is dominated by kinesin-1, but DDB and kinesin-1 are evenly matched, recapitulating recent experimental work. Kinesin-2 competes less well against dynein and DDB, and overall, load-dependent motor detachment is the property that most determines a motor's ability to compete in bidirectional transport. It follows that the most effective intracellular regulators of bidirectional transport are predicted to be those that alter motor detachment kinetics rather than motor velocity or stall force. K E Y W O R D S axon, dynein, Kinesin, microtubule, motor protein, neuron, optical tweezer, single-molecule, transport, vesicle

Renewal Reward Perspective on Linear Switching Diffusion Systems in Models of Intracellular Transport

“…As observed in recent studies, activated dynein competes more efficiently with kinesin, and therefore, the teams of opposite-directed motors are consistently slower than teams consisting of only the forward kinesin motor protein in Fig. 5b (Ohashi et al 2019). The expected run lengths in Fig.…”

“…On the other hand, activated dynein in the DDB complex is a more equal competitor to kinesin, with predictions of the expected run length in Fig. 5d confirming the experimental observations of larger unloaded run lengths in Ohashi et al (2019). Table 3 in "Appendix" for all parameters).…”

“…However, it has recently been shown that it might not be realistic to consider dynein in the absence of its helper proteins, particularly dynactin and BicD2. Together, these form a complex referred to as DDB, and the associated parameter values (Ohashi et al 2019) are much more "competitive" with kinesin-1 in a tug-of-war scenario (see Table 2 in "Appendix").…”

“…( 2008 , ( 2010 ) while panels ( b , d ) use dynein–dynactin–BicD2 (DDB) complex parameters as in Ohashi et al. ( 2019 ); see Table 2 in “Appendix” for all parameters. The run lengths in panels b and d are plotted on a log–log scale to allow for visualization of differences between the models considered.…”

Strain-Dependent Kinetic Properties of KIF3A and KIF3C Tune the Mechanochemistry of the KIF3AC Heterodimer

“…A recent study suggested that scaling of total force generation with the number of motors may happen more efficiently for kinesin-2 motors than in other kinesin subfamilies, suggesting that these motors may be adapted to drive transport in larger teams (54). The high probability of KIF3AC detachment from the microtubule under load along with the fast microtubule association kinetics of KIF3AC (4,17,18) would enable KIF3AC to navigate obstacles on the microtubule effectively (55) or transport cargo more efficiently in larger ensembles (56), (57,58).…”