Bicaudal D acts as a sensor to enable dynein-kinesin co-dependence

Cellular cargoes bind both the minus-end-directed motor dynein and the plus-end-directed motor kinesin, enabling bidirectional motion along microtubules. The molecular mechanism to explain why knocking down one motor abolishes motion in both directions, called the "paradox of co-dependence," remains enigmatic. Here, we use a model system consisting of dynein/dynactin and kinesin bound to the activating adaptor BicD to investigate this phenomenon. We demonstrate that run lengths are significantly increased when a full-length motor and a tail construct of the opposing motor are simultaneously bound to the same BicD, caused by an enhanced recruitment of two active motors to the complex. Notably, a registry-shifted point mutant of BicD (BicD^F684I) abolishes this increase in run length, suggesting that there is a sensing mechanism for motor binding that may be regulated by coiled-coil registry shifts within BicD. We also find that motile complexes are assembled more rapidly in the presence of the opposite-polarity motor, and that the resulting transport complexes are more stable. The necessity for the presence of opposing motors is thus not paradoxical but an advantageous strategy exploited by the cell to optimize transport efficiency.