Coil-to-a-helix transition at the Nup358-BicD2 interfaceactivates BicD2 for dynein recruitment
Abstract
Nup358, a protein of the nuclear pore complex, facilitates a nuclear positioning pathway that is essential for many biological processes, including neuromuscular and brain development. Nup358 interacts with the dynein adaptor Bicaudal D2 (BicD2), which in turn recruits the dynein machinery to position the nucleus. However, the molecular mechanisms of the Nup358/BicD2 interaction and the activation of transport remain poorly understood. Here for the first time, we show that a minimal Nup358 domain activates dynein/dynactin/BicD2 for processive motility on microtubules. Using nuclear magnetic resonance (NMR) titration and chemical exchange saturation transfer (CEST), mutagenesis and circular dichroism spectroscopy (CD), a Nup358 a-helix encompassing residues 2162-2184 was identified, which transitioned from a random coil to an a-helical conformation upon BicD2-binding and formed the core of the Nup358-BicD2 interface. Mutations in this region of Nup358 decreased the Nup358/BicD2 interaction, resulting in decreased dynein recruitment and impaired motility. BicD2 thus recognizes Nup358 though a 'cargo recognition a-helix', a structural feature that may stabilize BicD2 in its activated state and promote processive dynein motility.
Data availability
Protein backbone assignments have been deposited in the BMRB under accession code 5182. All other data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1, 2, 3, 4, 5, 6, 7, and 8.
Article and author information
Author details
Funding
NIH Office of the Director (R01 GM144578)
- M Yusuf Ali
- Sozanne R Solmaz
- Chunyu Wang
NIH Office of the Director (CA206592)
- Chunyu Wang
NIH Office of the Director (AG069039)
- Chunyu Wang
NIH Office of the Director (R15 GM128119)
- Sozanne R Solmaz
Chemistry Department and the Research Foundation of SUNY
- Sozanne R Solmaz
NIH Office of the Director (R35 GM136288)
- Kathleen M Trybus
NIH Office of the Director (R03 NS114115)
- M Yusuf Ali
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Preprint posted: May 7, 2021 (view preprint)
- Received: October 14, 2021
- Accepted: February 28, 2022
- Accepted Manuscript published: March 1, 2022 (version 1)
- Accepted Manuscript updated: March 4, 2022 (version 2)
- Version of Record published: March 25, 2022 (version 3)
- Version of Record updated: April 8, 2022 (version 4)
Copyright
© 2022, Gibson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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