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Activation of cytoplasmic dynein through microtubule crossbridging

Manas Chakraborty, Algirdas Toleikis, Nida Siddiqui, Robert A. Cross, Anne Straube

Preprint posted on April 13, 2020 https://www.biorxiv.org/content/10.1101/2020.04.13.038950v1

Walking on microtubule bundles gives dynein a power-up.

Selected by Mafalda Pimentel

Categories: biophysics, cell biology

Background

The dynein complex is mostly known as a molecular motor that transports cellular cargo along microtubules towards their minus-end. Yet, it has many other crucial roles, one of them being microtubule organization.

Each dynein complex has two heavy chains, with a motor unit at the respective C-terminus. These are typically regulated at the N-terminal tail region, where cargo adaptors can bind to increase dynein processivity1. Intriguingly, dynein’s ability to bind and slide two microtubules in opposing directions was shown to be independent of its tail domain2.

In this preprint, Chakraborty and colleagues sought to understand if microtubule binding can itself directly regulate the activity of mammalian dynein.

 

Key findings

It was known that dynein binds and slides microtubules, thus forming bundles of increased length2,3. The authors now observed that recombinant human dynein has the same in vitro behaviour. Additionally, they show that by sliding microtubules of opposing orientations, dynein ends up organizing them in parallel bundles over time.

They also provide further evidence for dynein binding 2 microtubules through its 2 motor domains: by attaching one of the microtubules to the coverslip, they detected dynein molecules moving at half the speed of the sliding microtubule. Instead, if one of the microtubules were carried by the tail region, dynein would have moved as much as the microtubule it slid or stayed fixed to the coverslip microtubule.

Interestingly, although human dynein has low intrinsic processivity on single microtubules, the authors noticed that long runs would often occur on bundles. To directly address if bundle bound dynein generated more power, they measured its strength using optical tweezers. Indeed, the average stall force of dynein on bundles was almost the double than on single microtubules.


Figure 1 – This work proposes that microtubule bridging by dynein, physically separates the motor domains that normally would autoinhibit each other when stacked4.

 

What I like about this work

I like this preprint because I believe that to fully understand the function of a key player such as dynein, we need to dissect its complex regulation with the experimental control that only in vitro allows. Using diverse approaches, Chakraborty et al. provided us another piece of the puzzle: while organizing microtubules, dynein is directly regulated by them.

 

Questions to the authors

It would be interesting to know if dynein processivity on bundles depends on microtubule orientation. This could provide some insight on dynein dynamics in contexts of mixed orientation microtubule arrays such as dendrites.

References
1. Kardon, J. R. & Vale, R. D. Regulators of the cytoplasmic dynein motor. Nature Reviews Molecular Cell Biology 10, 854–865 (2009).
2. Tanenbaum, M. E., Vale, R. D. & McKenney, R. J. Cytoplasmic dynein crosslinks and slides anti-parallel microtubules using its two motor domains. eLife 2, e00943 (2013).
3. Amos, L. A. Brain dynein crossbridges microtubules into bundles. Journal of Cell Science 93, 19–28 (1989).
4. Torisawa, T. et al. Autoinhibition and cooperative activation mechanisms of cytoplasmic dynein. Nature Cell Biology 16, 1118–1124 (2014).

Tags: dynein, microtubule organization, microtubule orientation, microtubules, molecular motors

Posted on: 12th May 2020

doi: https://doi.org/10.1242/prelights.19432

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Author's response

Anne Straube shared

Processivity refers to how many steps a single motor takes before it falls off a microtubule. For a single microtubule and a parallel bundle this is relatively easy to measure as it is proportional to the run length – assuming that step size is constant. In an antiparallel bundle where both microtubules are free to move, dynein would slide the bundle apart without being displaced itself and the length of bundle extension would be the combined action of all motors bound. Only if a single dynein mediates the sliding can we draw any conclusions as to its processivity. We do not have enough examples of single dynein sliding, to measure this. However, data from the Kapitein lab show that mixed polarity microtubules in dendrites exist in sub-bundles of uniform polarity (10.1016/j.neuron.2017.11.018). Thus we expect that within such a bundle, dynein will be able to use its crossbridging technique to walk with increased processivity. We believe that cargo-activated dynein, i.e. dynein in a complex with dynactin and a cargo adapter, will still benefit from crossbridging because data from the Carter lab show that the processivity of  dynein/dynactin/BicD2 complexes can be doubled by mutating surface residues that promote stacking of the motor domains (10.1016/j.cell.2017.05.025). We propose that crossbridging is as effective in keeping the motor domains unstacked.

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