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PreprintCited by 34Microtubule and mitosis dynamicsBiotin and Related StudiesGenomics and Chromatin Dynamics

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Conformational transitions of the mitotic adaptor Spindly underlie its interaction with Dynein and Dynactin

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d’Amico, Ennio, Ud Din Ahmad, Misbha, Cmentowski, Verena, Girbig, Mathias, Müller, Franziska, Wohlgemuth, Sabine, Brockmeyer, Andreas, Maffini, Stefano, Janning, Petra, Vetter, Ingrid R., Carter, Andrew P., Perrakis, Anastassis, Musacchio, Andrea·2022·The Journal of Cell Biology
DOI 10.1101/2022.02.02.478874PMC PMC9481740

Preprint — published as 10.1083/jcb.202206131 · Paper page

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Abstract

Cytoplasmic Dynein 1, or Dynein, is a microtubule minus-end directed motor. Dynein motility requires Dynactin and a family of activating adaptors that stabilize the Dynein-Dynactin complex and promote regulated interactions with cargo in space and time. How activating adaptors limit Dynein activation to specialized subcellular locales is unclear. Here, we reveal that Spindly, a mitotic Dynein adaptor at the kinetochore corona, exists natively in a closed conformation that occludes binding of Dynein-Dynactin to its CC1 box and Spindly motif. A structure-based analysis identified various mutations promoting an open conformation of Spindly that binds Dynein-Dynactin. A region of Spindly downstream from the Spindly motif and not required for cargo binding faces the CC1 box and stabilizes the intramolecular closed conformation. This region is also required for robust kinetochore localization of Spindly, suggesting that kinetochores promote Spindly activation to recruit Dynein. This mechanism may be paradigmatic for Dynein activation by other adaptors at various cellular locales.

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Metadata

Authors
d’Amico, E., Ud Din Ahmad, M., Cmentowski, V., Girbig, M., Müller, F., Wohlgemuth, S., Brockmeyer, A., Maffini, S., Janning, P., Vetter, I. R., Carter, A. P., Perrakis, A., & Musacchio, A.
Affiliations
  • Max Planck Institute of Molecular Physiology (DE)
  • MRC Laboratory of Molecular Biology (GB)
Corresponding author
Musacchio, Andrea
ORCID
Venue
The Journal of Cell Biology
Publisher
openRxiv
Published
2022-02-02
Volume
221
Issue
11
ISSN
0021-9525 (ISSN-L)
DOI
10.1101/2022.02.02.478874
PMC
PMC9481740
OpenAlex
W4295901867
Cited by
34
References
1
Citations by year
2026: 10 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 8
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (210711/Z/18/Z)
  • Deutsche Forschungsgemeinschaft (SFB 1430, 424228829)
  • Max-Planck-Gesellschaft
  • European Research Council (951439)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
SPINDLY, dynein, dynactin, conformational change, kinetochore, dynein activation, microtubule motor proteins, intramolecular binding, kinetochore localization, cargo binding
MeSH terms
Dynactin Complex, Protein Conformation, Kinetochores, Cell Cycle Proteins, Cytoplasmic Dyneins

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