Interplay between velocity and travel distance of kinesin-based transport in the presence of tau

📝 Abstract

Although the disease-relevant microtubule-associated protein tau is known to severely inhibit kinesin-based transport in vitro, the potential mechanisms for reversing this detrimental effect to maintain healthy transport in cells remain unknown. Here we report the unambiguous upregulation of multiple-kinesin travel distance despite the presence of tau, via decreased single-kinesin velocity. Interestingly, the presence of tau also modestly reduced cargo velocity in multiple-kinesin transport, and our stochastic simulations indicate that the tau-mediated reduction in single-kinesin travel underlies this observation. Taken together, our observations highlight a nontrivial interplay between velocity and travel distance for kinesin transport, and suggest that single-kinesin velocity is a promising experimental handle for tuning the effect of tau on multiple-kinesin travel distance.

💡 Analysis

Although the disease-relevant microtubule-associated protein tau is known to severely inhibit kinesin-based transport in vitro, the potential mechanisms for reversing this detrimental effect to maintain healthy transport in cells remain unknown. Here we report the unambiguous upregulation of multiple-kinesin travel distance despite the presence of tau, via decreased single-kinesin velocity. Interestingly, the presence of tau also modestly reduced cargo velocity in multiple-kinesin transport, and our stochastic simulations indicate that the tau-mediated reduction in single-kinesin travel underlies this observation. Taken together, our observations highlight a nontrivial interplay between velocity and travel distance for kinesin transport, and suggest that single-kinesin velocity is a promising experimental handle for tuning the effect of tau on multiple-kinesin travel distance.

📄 Content

Biophysical Journal-Biophysical Letters Biophysical Journal-Biophysical Letters L01 Interplay between Velocity and Travel Distance of Kinesin-based Transport in the Presence of Tau Jing Xu,* Stephen J King,† Maryse Lapierre-Landry,* Brian Nemec* *Physics Graduate Group, University of California, Merced, California, USA; †Burnett School of Biomedical Sciences, University of Central Florida, Florida, USA ABSTRACT Although the disease-relevant microtubule-associated protein tau is known to severely inhibit kinesin-based transport in vitro, potential mechanisms for reversing this detrimental effect to maintain healthy transport in cells remain unknown. Here we report the unambiguous up-regulation of multiple-kinesin travel distance despite the presence of tau, via decreased single-kinesin velocity. Interestingly, the presence of tau also modestly reduced cargo velocity in multiple-kinesin transport, and our stochastic simulations indicate that the tau-mediated reduction in single-kinesin travel underlies this observation. Taken together, our observations highlight a non-trivial interplay between velocity and travel distance for kinesin transport, and suggest that single-kinesin velocity is a promising experimental handle for tuning the effect of tau on multiple- kinesin travel distance. Received for publication “Staff will complete” and in final form “Staff will complete”
Address reprint requests and inquiries to: jing.xu@ucmerced.edu Conventional kinesin is a major microtubule-based molecular motor that enables long-range transport in living cells. Although traditionally investigated in the context of single-motor experiments, two or more kinesin motors are often linked together to transport the same cargo in vivo (1-4). Understanding the control and regulation of the group function of multiple kinesins has important implications for reversing failure modes of transport in a variety of human diseases, particularly neurodegenerative diseases. Tau is a disease-relevant protein enriched in neurons (5-6). The decoration of microtubules with tau is known to strongly inhibit kinesin transport in vitro (7-9), but how kinesin-based transport is maintained in the presence of high levels of tau, particularly in healthy neurons, remains an important open question. To date, no mechanism has been directly demonstrated to reverse the inhibitory effect of tau on kinesin-based transport. Here we present a simple in vitro study that demonstrates the significant up-regulation of multiple-kinesin travel distance with decreasing ATP concentration, despite the presence of tau. The current investigation was motivated by our recent finding that single-kinesin velocity is a key controller for multiple- kinesin travel distance along bare microtubules (10). The active stepping of each kinesin motor is stimulated by ATP (11), and each kinesin motor remains strongly bound to the microtubule between successive steps (10-11). As demonstrated for bare microtubules (10), with decreasing ATP concentrations, each microtubule-bound kinesin experiences a decreased stepping rate per unit time and spends an increased fraction of time in the strongly bound state; additional unbound kinesins on the same cargo have more time to bind to the microtubule before cargo travel terminates. Thus, reductions in single- kinesin velocity increase the probability that at least one kinesin motor will remain bound to the microtubule per unit time, thereby increasing the travel distance of each cargo (10). Since this effect only pertains to the stepping rate of each individual kinesin and does not address the potential presence of roadblocks such as tau on the microtubules, we hypothesized in the current study that single-kinesin velocity may be exploited to relieve the impact of tau on multiple- kinesin travel distance. We focused our in vitro investigation on human tau 23 (htau23, or 3RS tau), an isoform of tau that exhibits the strongest inhibitory effect on kinesin-based transport (7-9). Importantly, htau23 does not alter the stepping rate of individual kinesins (7, 9), supporting our hypothesis and enabling us to decouple single-kinesin velocity from the potential effects of tau. We carried out multiple-kinesin motility experiments using polystyrene beads as in vitro cargos (8, 10), ATP concentration as an in vitro handle to controllably tune single-kinesin velocity (10-11), and three input kinesin concentrations to test the generality of potential findings for multiple-kinesin transport. Combined with previous two-kinesin studies (10, 12), our measurements of travel distance (Fig. 1A) indicate that the lowest kinesin concentration employed (0.8 nM) corresponds to an average of ~2-3 kinesins per cargo. Note that in the absence of tau, the observed decrease in bead velocity at the higher kinesin concentrations (Fig. 1A) is consistent with a recent in vitro finding (13). At 1 mM ATP, htau23 reduced kinesin- based tra

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