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  • Title: Kinesin-1, -2, and -3 motors use family-specific mechanochemical strategies to effectively compete with dynein during bidirectional transport.
    Author: Gicking AM, Ma TC, Feng Q, Jiang R, Badieyan S, Cianfrocco MA, Hancock WO.
    Journal: Elife; 2022 Sep 20; 11():. PubMed ID: 36125250.
    Abstract:
    Bidirectional cargo transport in neurons requires competing activity of motors from the kinesin-1, -2, and -3 superfamilies against cytoplasmic dynein-1. Previous studies demonstrated that when kinesin-1 attached to dynein-dynactin-BicD2 (DDB) complex, the tethered motors move slowly with a slight plus-end bias, suggesting kinesin-1 overpowers DDB but DDB generates a substantial hindering load. Compared to kinesin-1, motors from the kinesin-2 and -3 families display a higher sensitivity to load in single-molecule assays and are thus predicted to be overpowered by dynein complexes in cargo transport. To test this prediction, we used a DNA scaffold to pair DDB with members of the kinesin-1, -2, and -3 families to recreate bidirectional transport in vitro, and tracked the motor pairs using two-channel TIRF microscopy. Unexpectedly, we find that when both kinesin and dynein are engaged and stepping on the microtubule, kinesin-1, -2, and -3 motors are able to effectively withstand hindering loads generated by DDB. Stochastic stepping simulations reveal that kinesin-2 and -3 motors compensate for their faster detachment rates under load with faster reattachment kinetics. The similar performance between the three kinesin transport families highlights how motor kinetics play critical roles in balancing forces between kinesin and dynein, and emphasizes the importance of motor regulation by cargo adaptors, regulatory proteins, and the microtubule track for tuning the speed and directionality of cargo transport in cells. Nerve cells in the human body can reach up to one meter in length. Different regions of a nerve cell require different materials to perform their roles. The motor proteins kinesins and dynein help to transport the required ‘cargo’, by moving in opposite directions along tracks called microtubules. However, many cargos have both motors attached, resulting in a tug-of-war to determine which direction and how fast the cargo will travel. In many neurodegenerative diseases, including Alzheimer’s, this cargo transport goes awry, so a better understanding of exactly how this process works may help to develop new therapies. There are three families of kinesin motors, for a total of about a dozen different kinesins that engage in this process. Motors in each of the three families have different mechanical properties. Specific cargos also tend to have specific kinesins attached to them. Here Gicking et al. hypothesized that when pulling against dynein in a tug-of-war, kinesins from the three families would behave differently. To test this hypothesis, Gicking et al. linked one kinesin to one dynein motor, one at a time in a test tube, and then observed how these two-motor complexes moved using fluorescence microscopy techniques. Unexpectedly, kinesins from the three different families competed similarly against dynein: there were no clear winners and losers. By incorporating previously published data describing the different motor behaviors, Gicking et al. developed a computational model that provided deeper insight into how this mechanical tug-of-war works. The modeling indicated that kinesins from the three families use different approaches for competing against dynein. Kinesin-1 motors tended to pull steadily against dynein, only detaching relatively rarely, but then take some time to attach back to the microtubule track. In contrast, kinesin-3 motors detached easily when they pull against dynein, but they attach back to the microtubule track quickly, taking only about a millisecond to start moving again. Kinesin-2 motors exhibited an intermediate behavior. Overall, these experiments suggest that the mechanical properties of the motor proteins are not the main factors determining the direction and speed of the cargo. In other words, the outcome of this molecular tug-of-war does not necessarily depend on which motor is stronger or faster. Rather, further mechanisms, including regulation of the adapter molecules that connect the motors to their cargo, may help to regulate which cargo go where in branched nerve cells. A better knowledge of how all these different factors work together will be important for understanding how cargo transport in nerve cells is disrupted in neurodegenerative diseases.
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