Lee Robert H, Mitchell Cassie S
Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
J Theor Biol. 2015 Apr 7;370:39-44. doi: 10.1016/j.jtbi.2015.01.010. Epub 2015 Jan 20.
Cargos have been observed exhibiting a "stop-and-go" behavior (i.e. cargo "pause"), and it has generally been assumed that these multi-second pauses can be attributed to equally long pauses of cargo-bound motors during motor procession. We contend that a careful examination of the isolated microtubule experimental record does not support motor pauses. Rather, we believe that the data suggests that motor cargo complexes encounter an obstruction that prevents procession, eventually detach and reattach, with this obstructed-detach-reattach sequence being observed in axon as a "pause." Based on this, along with our quantitative evidence-based contention that slow and fast axonal transport are actually single and multi-motor transport, we have developed a cargo level motor model capable of exhibiting the full range of slow to fast transport solely by changing the number of motors involved. This computational model derived using first-order kinetics is suitable for both kinesin and dynein and includes load-dependence as well as provision for motors encountering obstacles to procession. The model makes the following specific predictions: average distance from binding to obstruction is about 10 μm; average motor maximum velocity is at least 6 μm/s in axon; a minimum of 10 motors is required for the fastest fast transport while only one motor is required for slow transport; individual in-vivo cargo-attached motors may spend as little as 5% of their time processing along a microtubule with the remainder being spent either obstructed or unbound to a microtubule; and at least in the case of neurofilament transport, kinesin and dynein are largely not being in a "tug-of-war" competition.
人们观察到货物表现出“走走停停”的行为（即货物“暂停”），并且通常认为这些持续数秒的暂停可归因于货物结合的马达在行进过程中同样长时间的暂停。我们认为，仔细检查孤立微管的实验记录并不支持马达暂停的观点。相反，我们认为数据表明马达货物复合物遇到阻碍其行进的障碍物，最终分离并重新附着，这种受阻 - 分离 - 重新附着的序列在轴突中被观察为“暂停”。基于此，再加上我们基于定量证据的观点，即慢速和快速轴突运输实际上是单马达和多马达运输，我们开发了一种货物水平的马达模型，仅通过改变所涉及的马达数量就能展现出从慢速到快速运输的整个范围。这个使用一阶动力学推导的计算模型适用于驱动蛋白和动力蛋白，包括负载依赖性以及考虑到马达遇到行进障碍物的情况。该模型做出了以下具体预测：从结合到障碍物的平均距离约为10μm；轴突中马达的平均最大速度至少为6μm/s；最快的快速运输至少需要10个马达，而慢速运输仅需一个马达；单个体内附着货物的马达沿微管行进的时间可能仅占其总时间的5%，其余时间则处于受阻状态或未与微管结合；至少在神经丝运输的情况下，驱动蛋白和动力蛋白在很大程度上不存在“拔河”竞争。
