The mammalian dynein–dynactin complex is a strong opponent to kinesin in a tug-of-war competition

Abstract

Kinesin and dynein motors transport intracellular cargos bidirectionally by pulling them in opposite directions along microtubules, through a process frequently described as a ‘tug of war’. While kinesin produces a 6 pN force, mammalian dynein was found to be a surprisingly weak motor (0.5–1.5 pN) in vitro, suggesting many dyneins are required to counteract the pull of a single kinesin. Mammalian dynein’s association with dynactin and Bicaudal-D2 (BICD2) activates its processive motility, but how this affects dynein’s force output remained unknown. Here, we show that formation of the dynein-dynactin-BICD2 (DDB) complex increases human dynein’s force production to 4.3 pN. An in vitro tug-of-war assay revealed that a single DDB successfully resists a single kinesin. Contrary to previous reports, the clustering of many dyneins is not required to win the tug-of-war. Our work reveals the key role of dynactin and a cargo adaptor protein in shifting the balance of forces between dynein and kinesin motors during intracellular transport.

Intracellular cargo transport by kinesin-3 motors

“…Potential linkers to facilitate cooperation of dynein and kinesin 3 include Hook and Bicaudal, cargo adapter proteins that have been identified to interact with both dynein and kinesin 3 tail domains [41,69,125,126]. Interestingly, the presence of BICD2 increases the force generation and processivity of dynein/dynactin [127,128], demonstrating that these cargo adapter proteins regulate motor activity and could act as switches to control transport directionality within a complex containing two opposing motors. Other control mechanisms could come from accessory proteins such as kinesin binding protein (KBP), which has been shown to stimulate KIF1B, but inhibit KIF1A mediated bidirec tional transport [28,129].…”

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

“…Whereas individual mammalian dyneins in vitro very rarely exhibit processive behavior (the ability to take repeated steps along microtubules) (25)(26)(27)(28), dynein complexes bound to the accessory complex dynactin and a cargo adaptor frequently move processively over very long distances (25,(28)(29)(30). Once bound to dynactin and a cargo adaptor, processive movements of dynein are faster and the motor has a greater force output (28,31).…”

Tug-of-war between two elastically coupled molecular motors: a case study on force generation and force balance

“…Very recently, it has also been demonstrated that one can directly crosslink a single, fluo-labeled kinesin with a single, fluo-labeled dynein via DNA hybridization. 21 Our tug-of-war model provides detailed predictions for the transport properties of such a two-motor system. One of these properties is the probability distribution p st j for the spatial separation of the two motors as displayed in Fig.…”

“…The fluctuating motor-motor separation L should be directly accessible to experimental studies when one combines the recently introduced crosslinking of one fluo-labeled kinesin and one fluo-labeled dynein via DNA hybridization 21 with advanced methods of fluorescence imaging such as FIONA. 29 In Fig.…”

“…Very recently, it has also been demonstrated that one can directly crosslink a single, fluo-labeled kinesin with a single, fluo-labeled dynein via DNA hybridization. 21 For such two-motor constructs, one should be able to measure the probability distribution for the spatial separation of the two motors along the filament and, in this way, directly scrutinize the predictions of our theory. Furthermore, as shown below, the distribution for the motor-motor separation also determines the probability distribution for the elastic interaction forces and, thus, the average elastic force hFi between the motors.…”