Activation of cytoplasmic dynein through microtubule crossbridging
Posted on: 12 May 2020
Preprint posted on 13 April 2020
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).
doi: https://doi.org/10.1242/prelights.19432
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