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Vision: As one FDOT team, we serve the people of Florida by providing a transportation network that is well planned, supports economic growth, and has the goal of being congestion and fatality free.
Yet, some progress has been made. Share the Road, a United Nations Environment Programme-led initiative launched in 2008, advocates for investments in walking and cycling infrastructure, including links to public transport systems. The initiative has promoted non-motorized transport programmes in Mexico, Brazil, Ghana, Nigeria, Zambia, Ethiopia, Kenya, Rwanda, Burundi, Uganda, and Indonesia. It also collaborated with the Institute for Transportation and Development Policy (ITDP) to create a toolkit for developing non-motorized policies and strategies (FIA Foundation, 2020).
Within cells, motor and non-motor microtubule-associated proteins (MAPs) simultaneously converge on the microtubule. How the binding activities of non-motor MAPs are coordinated and how they contribute to the balance and distribution of motor transport is unknown. Here, we examine the relationship between MAP7 and tau owing to their antagonistic roles in vivo. We find that MAP7 and tau compete for binding to microtubules, and determine a mechanism by which MAP7 displaces tau from the lattice. MAP7 promotes kinesin-based transport in vivo and strongly recruits kinesin-1 to the microtubule in vitro, providing evidence for direct enhancement of motor motility by a MAP. Both MAP7 and tau strongly inhibit kinesin-3 and have no effect on cytoplasmic dynein, demonstrating that MAPs differentially control distinct classes of motors. Overall, these results reveal a general principle for how MAP competition dictates access to the microtubule to determine the correct distribution and balance of motor activity.
Here, we present a detailed analysis of the competition between tau and MAP7 and a molecular dissection of the functional interaction between MAP7 and kinesin-1. We find that MAP7 actively competes with and displaces tau from the microtubule, and determine a molecular mechanism by which MAP7 invades and displaces tau from the lattice. In striking contrast to the inhibitory effect of tau, MAP7 promotes kinesin-based transport in vivo and enhances kinesin-1 binding to the microtubule 150-fold in vitro, providing evidence for direct regulation of a motor by a MAP. In addition, we find that MAP7 and tau strongly inhibit kinesin-3, but have no effect on dynein motility, suggesting that individual MAPs may provide differential control over distinct classes of microtubule motors. Our work illustrates a general principle for how competition between microtubule-associated proteins directs and distributes molecular motors to maintain a balance of transport within the crowded intracellular environment.
Overall, our study presents a detailed analysis of the competition between tau and MAP7 and a molecular dissection of the functional interaction between MAP7 and kinesin-1. Previous studies have shown that tau inhibits kinesin-1 without markedly affecting dynein9,10, posing a transport problem within the axons of neuronal cells (Fig. 6h). We have found that MAP7 can facilitate kinesin-1 motility in two ways without significantly affecting dynein. First, MAP7 actively competes with and displaces tau from the microtubule, and second, MAP7 directly recruits kinesin-1 to the microtubule (Fig. 6h). It has been proposed that MAP7 relieves the autoinhibition of kinesin-1 in vivo16. Whether MAP7 has a secondary role in relieving the autoinhibition of kinesin-1 either in solution or after recruitment to the microtubule will be an interesting line of future investigation. We further show that both MAP7 and tau inhibit kinesin-3, which transports cargo into both dendrites and axons (Fig. 6h). The differential effects of these MAPs on microtubule motors not only establishes the balance of kinesin-1 and dynein transport in the axon, but may also help to direct kinesin-3 motors into the dendrites during specific developmental stages.
Our results also raise intriguing questions about competition between other MAPs. The microtubule-binding domain of MAP7 is distinct from that of tau, MAP2, and MAP4, which contain similar tandem microtubule-binding repeats39. Based on our results, it is possible that tau and MAP7 also compete with other MAPs for microtubule binding. Competition or coordination between MAP7 and dendrite-specific MAPs, such as MAP2 or DCX, may be especially important for directing kinesin-3 transport, because MAP7 is present in the dendrites, but inhibits kinesin-3 in vitro. Likewise, there may be axonal MAPs that enable kinesin-3 to drive transport in the axons in the presence of both MAP7 and tau. Additionally, there are other mechanisms of regulation that could dictate the spatiotemporal association patterns of MAPs on microtubules, such as post-translational modifications of tubulin40 or of the MAPs themselves. Overall, our results suggest that competition between MAPs may be a general mechanism for directing motor transport in cells. Combined with the tubulin-code hypothesis, which posits that modifications of the tubulin subunits themselves modulate molecular motor transport40,41, our data contributes another layer of regulation, the MAP-code, that we suggest may be similarly effectual in the spatiotemporal control of intracellular transport. 153554b96e