July 18, 2008 | David F. Coppedge

Cellular Trucks Use Moving Highways

Imagine how cool it would be to get in your car and have the road do the driving.  The highway would stretch or shrink, moving this way or that, till you saw your destination and hopped off.  That appears to be what the cargo-bearing motors do in the cells in your body.  A new paper by a team of American biophysicists published the hypothesis in PNAS this week.1
    Cell biologists have known for a long time that molecular motors move cargo around on long strands of protein, called microtubules, that form an intracellular highway network (12/04/2003) called the cytoskeleton.  One observation that has been confusing, though, is why the motors seem to just move back and forth (bidirectional transport) instead of making progress toward a destination.  It doesn’t seem to make any sense.  Would a car that has to get somewhere just keep shifting between forward and reverse gears?  It starts to make better sense when you consider that the road is also doing the moving.
    The situation in a cell is much more complex than suggested above.  The cell is a crowded environment, with enzymes and parts moving about rapidly.  In addition, there is thermal motion adding to the hustle and bustle.  Microtubules grow and shrink as their molecular components are added and removed constantly.  Cargo-carrying motors, like dynein and kinesin, attach and detach from their freeways all the time.  It seems chaotic, but the cell works.  Somehow it is a powerhouse of organization and function.
    The authors of this new idea proposed that any given cargo vesicle has multiple motors attached to multiple tracks at a time.  These motors can work in concert, tugging on the microtubules, making them bend and buckle at times.  Think of what could happen if cars could do this on a 3-D freeway system, in which they had attachments to multiple tracks at once.  They could compress the road, let go of the overhead track, and then shoot out quickly for miles as the road beneath them stretched back to its extended position.  Some vehicles along for the ride could get a free ride – like on a moving sidewalk that advances by un-stretching itself.
    Is this a novel concept, or what?  Here’s how the authors explained it, after first dismissing other possibilities:

Given these observations, a more parsimonious explanation is that nonthermal (motor-induced) forces and quenched disorder constraining the microtubule backbones within the cell body generate large backbone undulations.  Numerous constraints are imposed by the crowded intracellular environment, forcing the microtubule backbone into an effective highly curved confining tube, in particular through entanglement with other microtubules.  The large stored length of microtubules (within the cell body) is transmitted over long distances by the virtually incompressible microtubules and projected in the longitudinal direction inside the processes…. … The fluctuating tensions are induced by multiple molecular motors decorating intracellular cargos and cross-bridging between several microtubules at a time.
    The microtubule network actively “animated” in this fashion induces an additional velocity component that adds to the motor-driven cargo transport velocities in the microtubule fixed reference frame.

A cell’s molecular motors thus drive the road as well as the car!  With this mechanism, they get a velocity boost that helps them arrive at their destinations faster than if they simply moved along the microtubule at constant velocity.  This also begins to explain why the motors move back and forth:

As suggested by our data, within the “fluctuating cytoskeleton” picture we can indeed understand the observed back-and-forth motion as a consequence of a peculiar form of tug of war of many motors competing with each other and with microtubule elastic forces.  As opposed to the “local” tug of war of opposite polarity motors on the same vesicle, the “global” tug of war described here allows large numbers of motors distributed along the whole microtubule to exert forces at a time and compete for the direction of microtubule movement.  When bent on large scales, the microtubules offer a rather large compliance to the exerted longitudinal and lateral forces, which in turn allows all of the motors along their length to act at a time and generate the observed microtubule fluctuations.  Switching of motor pulling and microtubule relaxation phases can induce a back-and-forth motion of the microtubule backbone.

But a question remains.  How does this help the motor get its attached cargo get to its destination?  Simple: it hitchhikes.  This is actually the term they suggested to describe their hypothesis.  Some motors only need a short hop.  They grab the moving microtubule and let go when they need to.  Others, needing rapid transit across longer distances, play the system by binding and unbinding repeatedly.  In a matter of seconds, the motor can cover a long distance (relative to its own tiny size).  The moving-sidewalk system even works for cargos without their own motors.  “For this mode of motility involving transient binding of cargos to moving microtubules, which eventually leads to a long-range dispersion, we suggest the term ‘hitchhiking,’” they said.  “Exploiting this simple mechanism, even cargos devoid of active motors can be efficiently dispersed throughout the entire cell.”  In short,“We demonstrate that, besides being tracks for motors that directly haul cargos, microtubules can transmit the force of distant motors onto a cargo over large separations.2

1.  Kulik, Brown, Kim, Kural, Blehm, Selvin, Nelson and Gelfand, “The role of microtubule movement in bidirectional organelle transport,” Proceedings of the National Academy of Sciences USA, Published online before print July 14, 2008, doi: 10.1073/pnas.0800031105.
2.  Physicists may enjoy this extra detail:   This implies a mechanical nonlocality of the cytoskeleton because a longitudinal pulling strain in an almost stretched microtubule is essentially instantaneously transmitted over long distances.  Furthermore, microtubule motion on intermediate timescales (tens of milliseconds to several seconds) can be understood as a consequence of pulling out the slack length of microtubules induced by random constraints and motor forces along its entire length.”

Frequent readers of CEH will know immediately the answer to this pop quiz question.  “True or false: evolution was mentioned in this paper.” (Answer: false).
    As amazing as this explanation was, other questions come to mind.  How does the motor know where to get on and off?  How do the motors conspire to control the microtubules for best effect?  Remember, these are blind molecules in a busy, seemingly chaotic environment.  The results, however, are anything but chaotic.  There are wonders in this black box we are only beginning to appreciate.

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