The Power of Three: Dynactin associates with three dyneins under load for greater force production
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Cytoplasmic dynein is an essential microtubule motor protein that powers organelle transport and mitotic spindle assembly. Its activity depends on dynein-dynactin-cargo adaptor complexes, such as dynein-dynactin-BicD2 (DDB), which typically function with two dynein motors. We show that mechanical tension recruits a third dynein motor via an auxiliary BicD adaptor binding the light intermediate chain of the third dynein, stabilizing multi-dynein assemblies and enhancing force generation. Lis1 prevents dynein from transitioning into a force-limiting phi-like conformation, allowing single-dynein DDB to sustain forces up to ∼4.5 pN, whereas force generation often ends at ∼2.5 pN without Lis1. Complexes with two or three dyneins generate ∼7 pN and ∼9 pN, respectively, consistent with a staggered motor arrangement that enhances collective output. Under load, DDB primarily takes ∼8 nm steps, challenging existing dynein coordination models. These findings reveal adaptive mechanisms that enable robust intracellular transport under varying mechanical demands.