Bidirectional cargo transport: moving beyond tug of war

Key Points

  • Diverse intracellular cargos are transported along microtubules by the actions of kinesin and dynein molecular motors.

  • The 'tug-of-war' model describes bidirectional movement as a mechanical competition between kinesins and dyneins. This model is supported by both theoretical and experimental studies.

  • There are several studies in which inhibiting one motor was found to suppress transport in both directions, contrary to predictions from the tug-of-war model. This phenomenon is termed the 'paradox of co-dependence' of antagonistic motors.

  • Three hypothetical mechanisms are proposed to reconcile this paradox: microtubule tethering, mechanical activation and steric disinhibition. Each makes specific predictions regarding directional switching and the nature of the pause states.

  • A more complete understanding of bidirectional transport will require mathematical modelling to both frame the best experiments and interpret quantitative data. The three hypothetical mechanisms, and other potential mechanisms, can be incorporated into a common modelling framework.

Abstract

Vesicles, organelles and other intracellular cargo are transported by kinesin and dynein motors, which move in opposite directions along microtubules. This bidirectional cargo movement is frequently described as a 'tug of war' between oppositely directed molecular motors attached to the same cargo. However, although many experimental and modelling studies support the tug-of-war paradigm, numerous knockout and inhibition studies in various systems have found that inhibiting one motor leads to diminished motility in both directions, which is a 'paradox of co-dependence' that challenges the paradigm. In an effort to resolve this paradox, three classes of bidirectional transport models — microtubule tethering, mechanical activation and steric disinhibition — are proposed, and a general mathematical modelling framework for bidirectional cargo transport is put forward to guide future experiments.

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Figure 1: Three classes of bidirectional transport in cells.
Figure 2: The tug-of-war model.
Figure 3: Different mechanisms for the pause state.
Figure 4: Examples of antagonistic motor co-dependence.
Figure 5: Three hypothetical mechanisms for resolving the paradox of co-dependence.
Figure 6: Mathematical modelling framework for bidirectional transport models.

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Acknowledgements

The hypothetical models defined here were developed and refined during discussions with J. Fricks, P. Kramer and S. McKinley. D. Arginteanu provided assistance with figures and members of the Hancock laboratory provided helpful comments. W.O.H. is supported by the US National Institutes of Health (NIH) grant R01GM076476.

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PowerPoint slides

Glossary

Amyloid-β precursor protein

(APP). A protein that is proteolyzed to generate amyloid β (A4) protein, which forms plaques in Alzheimer's disease.

Prion protein

The protein responsible for transmissible spongiform encephalopathy (including scrapie and mad cow disease).

Myosin V

A processive myosin motor involved in cargo transport along actin filaments.

Optical tweezers

An experimental technique that uses light to trap and manipulate transparent objects, which enables measurements of forces and displacements.

Processivity

The ability of a motor to walk many steps along its filament before detaching.

Sister kinetochores

Regions of duplicated chromosomes that interact with microtubules and regulate chromosome movement during mitosis.

Mean field computational model

A model in which all of the molecular motors of a particular type are assumed to share the mechanical load equally and step in unison.

Run length

The distance a molecular motor moves before detaching from the filament and diffusing away.

Stall force

The force against which a motor cannot walk any further.

Kymograph

A graphical presentation of spatial position over time that uses data from a stack of images or movie. The intensity profile along a line is recorded for every image in the stack, and the lines are assembled to create an image in which the distance is displayed on one axis and time on the other.

Substall

Forces that are less than the stall force of a molecular motor. They enable the forward 'stepping' of motors.

Superstall

Forces that are greater than the stall force of a molecular motor. They cause motors to either remain stationary, walk backwards or detach.

Centroid tracking

A method used to determine the position of an object in a microscope image and to follow its change in position in successive images. The centroid is also known as the centre of mass.

Aplysia spp.

A genus of sea slugs that is used as a model system in neurobiology.

Catch bond

The dissociation rate of this type of bond decreases (the bond strength increases) with increased pulling forces.

Mean-squared displacement

A parameter commonly used to measure diffusion. It is calculated by squaring the displacement of an object from its original position. Its rate of change with time is proportional to the diffusion constant.

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Hancock, W. Bidirectional cargo transport: moving beyond tug of war. Nat Rev Mol Cell Biol 15, 615–628 (2014). https://doi.org/10.1038/nrm3853

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