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Sorting out microtubule-based transport

Nature Reviews Molecular Cell Biology volume 22, page 73 (2021)Cite this article

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To move inside cells, organelles and large macromolecular assemblies either need to be streamlined by cytoplasmic flow or transported as cargo by molecular motors along the cytoskeleton. Kinesin and dynein are two classes of motors that are specialized in cargo trafficking along microtubules. Despite decades of extensive research, our understanding of how these motors are recruited to specific cargoes and how cargoes are delivered to their correct destinations remains incomplete.

Early in vitro studies characterizing motor activity of cytoplasmic dynein were especially puzzling, as they showed dynein to be an exceptionally weak motor exhibiting little to no movement along microtubules. This was in stark contrast to the robust transport of dynein-driven cargoes in the cells. In vivo studies identified several dynein cofactors, such as dynactin or LIS1, but these factors were not sufficient to stimulate dynein movement in vitro, suggesting that other regulatory proteins are required for dynein motor activity. The turning point that started to solve this puzzle was a seminal paper by Akhmanova (Splinter et al. 2012), showing that the N-terminal coiled-coil of a protein BICD2 strengthens the interaction between dynein and dynactin and activates dynein motility in cells, thereby establishing BICD2 as a bona fide adaptor for dynein. This was followed by two elegant in vitro reconstitution studies by Vale (McKenney et al. 2014), and Carter and Bullock (Schlager et al. 2014), demonstrating that the reconstituted dynein–dynactin–adaptor complexes are able to move on microtubules long distances and with speeds comparable to dynein-driven cargoes in cells. Subsequent work characterized further adaptor proteins that link dynein to different cargoes and revealed the structural and biophysical mechanism of adaptor-mediated activation of dynein motility (see Reck-Peterson et al. 2018 for Review). At least some of these adaptors also recruit plus-end directed kinesins, highlighting the possibility that the adaptor proteins regulate the activities of opposite polarity motors to determine which direction the cargo moves.

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References

Original articles

  • Splinter, D. et al. BICD2, dynactin, and LIS1 cooperate in regulating dynein recruitment to cellular structures. Mol. Biol. Cell 23, 4226–4241 (2012)

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  • Schlager, M. A. et al. In vitro reconstitution of a highly processive recombinant human dynein complex. EMBO J. 33, 1855–1868 (2014)

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Related article

  • Reck-Peterson, S. L. et al. The cytoplasmic dynein transport machinery and its many cargoes. Nat. Rev. Mol. Cell Biol. 19, 382–398 (2018)

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  1. Physics Department and Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, USA

    Ahmet Yildiz

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  1. Ahmet Yildiz
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Correspondence to Ahmet Yildiz.

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Yildiz, A. Sorting out microtubule-based transport. Nat Rev Mol Cell Biol 22, 73 (2021). https://doi.org/10.1038/s41580-020-00320-y

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