Directionality of dynein is controlled by the angle and length of its stalk

Sinan Can; Samuel Lacey; Mert Gur; Andrew P. Carter; Ahmet Yildiz

doi:10.1038/s41586-019-0914-z

Directionality of dynein is controlled by the angle and length of its stalk

Sinan Can, Samuel Lacey, Mert Gur, Andrew P. Carter, Ahmet Yildiz^*

^*Corresponding author for this work

Department of Mechanical Engineering

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

Abstract

The ability of cytoskeletal motors to move unidirectionally along filamentous tracks is central to their role in cargo transport, motility and cell division. Kinesin and myosin motor families have a subclass that moves towards the opposite end of the microtubule or actin filament with respect to the rest of the motor family^1,2, whereas all dynein motors that have been studied so far exclusively move towards the minus end of the microtubule³. Guided by cryo-electron microscopy and molecular dynamics simulations, we sought to understand the mechanism that underpins the directionality of dynein by engineering a Saccharomyces cerevisiae dynein that is directed towards the plus end of the microtubule. Here, using single-molecule assays, we show that elongation or shortening of the coiled-coil stalk that connects the motor to the microtubule controls the helical directionality of dynein around microtubules. By changing the length and angle of the stalk, we successfully reversed the motility towards the plus end of the microtubule. These modifications act by altering the direction in which the dynein linker swings relative to the microtubule, rather than by reversing the asymmetric unbinding of the motor from the microtubule. Because the length and angle of the dynein stalk are fully conserved among species, our findings provide an explanation for why all dyneins move towards the minus end of the microtubule.

Original language	English
Pages (from-to)	407-410
Number of pages	4
Journal	Nature
Volume	566
Issue number	7744
DOIs	https://doi.org/10.1038/s41586-019-0914-z
Publication status	Published - 21 Feb 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

Acknowledgements We thank F. B. Cleary, H. Schmidt, C. Cypranowska, V. Belyy and L. Ferro for initiation of this project; S. Chen, C. Savva, G. Cannone, J. Grimmett, T. Darling and L. Kellogg for technical assistance with cryo-EM; M. Mofrad and M. Mehrbod for coarse-grained simulations; and the Savio Cluster for molecular dynamics simulations. This work was funded by grants from the NIH (GM094522), and NSF (MCB-1055017, MCB-1617028) to A.Y., the Wellcome Trust (WT100387) and the Medical Research Council, UK (MC_UP_ A025_1011) to A.P.C., and TUBITAK (215Z398) and ITU BAP (38777) to M.G.

Funders	Funder number
ITU BAP	38777
TUBITAK	215Z398
National Science Foundation	MCB-1617028, MCB-1055017
National Institutes of Health
National Institute of General Medical Sciences	R01GM094522
Wellcome Trust	WT100387
Medical Research Council	MC_UP_ A025_1011

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title = "Directionality of dynein is controlled by the angle and length of its stalk",

abstract = "The ability of cytoskeletal motors to move unidirectionally along filamentous tracks is central to their role in cargo transport, motility and cell division. Kinesin and myosin motor families have a subclass that moves towards the opposite end of the microtubule or actin filament with respect to the rest of the motor family1,2, whereas all dynein motors that have been studied so far exclusively move towards the minus end of the microtubule3. Guided by cryo-electron microscopy and molecular dynamics simulations, we sought to understand the mechanism that underpins the directionality of dynein by engineering a Saccharomyces cerevisiae dynein that is directed towards the plus end of the microtubule. Here, using single-molecule assays, we show that elongation or shortening of the coiled-coil stalk that connects the motor to the microtubule controls the helical directionality of dynein around microtubules. By changing the length and angle of the stalk, we successfully reversed the motility towards the plus end of the microtubule. These modifications act by altering the direction in which the dynein linker swings relative to the microtubule, rather than by reversing the asymmetric unbinding of the motor from the microtubule. Because the length and angle of the dynein stalk are fully conserved among species, our findings provide an explanation for why all dyneins move towards the minus end of the microtubule.",

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Directionality of dynein is controlled by the angle and length of its stalk

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