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Cryo-EM captures early intermediate steps in dynein activation by LIS1

Author

Listed:
  • Kendrick H. V. Nguyen

    (University of California San Diego)

  • Eva P. Karasmanis

    (University of California San Diego)

  • Agnieszka A. Kendrick

    (Salk Institute for Biological Studies)

  • Samara L. Reck-Peterson

    (University of California San Diego
    University of California San Diego
    Howard Hughes Medical Institute)

  • Andres E. Leschziner

    (University of California San Diego
    University of California San Diego)

Abstract

Cytoplasmic dynein-1 (dynein) is an essential molecular motor in eukaryotic cells. Dynein primarily exists in an autoinhibited Phi state and requires conformational changes to assemble with its cofactors and form active transport complexes. LIS1, a key dynein regulator, enhances dynein activation and assembly. Using cryo-EM and a human dynein-LIS1 sample incubated with ATP, we map the conformational landscape of dynein activation by LIS1 and identify an early intermediate state that we propose precedes the previously identified dynein-LIS1 Chi state. Mutations that disrupt this species, which we termed “Pre-Chi”, lead to motility defects in vitro, emphasizing its functional importance. Together, our findings provide insights into how LIS1 relieves dynein autoinhibition during the activation pathway.

Suggested Citation

  • Kendrick H. V. Nguyen & Eva P. Karasmanis & Agnieszka A. Kendrick & Samara L. Reck-Peterson & Andres E. Leschziner, 2025. "Cryo-EM captures early intermediate steps in dynein activation by LIS1," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62185-z
    DOI: 10.1038/s41467-025-62185-z
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