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A 5+1 assemble-to-activate mechanism of the Lon proteolytic machine

Author

Listed:
  • Shanshan Li

    (University of Science and Technology of China)

  • Kan-Yen Hsieh

    (Institute of Biological Chemistry, Academia Sinica)

  • Chiao-I Kuo

    (Institute of Biological Chemistry, Academia Sinica)

  • Tzu-Chi Lin

    (Institute of Biological Chemistry, Academia Sinica)

  • Szu-Hui Lee

    (Institute of Biological Chemistry, Academia Sinica)

  • Yi-Ru Chen

    (Institute of Biological Chemistry, Academia Sinica)

  • Chun-Hsiung Wang

    (Institute of Biological Chemistry, Academia Sinica)

  • Meng-Ru Ho

    (Institute of Biological Chemistry, Academia Sinica)

  • See-Yeun Ting

    (Institute of Molecular Biology, Academia Sinica)

  • Kaiming Zhang

    (University of Science and Technology of China)

  • Chung-I Chang

    (Institute of Biological Chemistry, Academia Sinica
    National Taiwan University)

Abstract

Many AAA+ (ATPases associated with diverse cellular activities) proteins function as protein or DNA remodelers by threading the substrate through the central pore of their hexameric assemblies. In this ATP-dependent translocating state, the substrate is gripped by the pore loops of the ATPase domains arranged in a universal right-handed spiral staircase organization. However, the process by which a AAA+ protein is activated to adopt this substrate-pore-loop arrangement remains unknown. We show here, using cryo-electron microscopy (cryo-EM), that the activation process of the Lon AAA+ protease may involve a pentameric assembly and a substrate-dependent incorporation of the sixth protomer to form the substrate-pore-loop contacts seen in the translocating state. Based on the structural results, we design truncated monomeric mutants that inhibit Lon activity by binding to the native pentamer and demonstrated that expressing these monomeric mutants in Escherichia coli cells containing functional Lon elicits specific phenotypes associated with lon deficiency, including the inhibition of persister cell formation. These findings uncover a substrate-dependent assembly process for the activation of a AAA+ protein and demonstrate a targeted approach to selectively inhibit its function within cells.

Suggested Citation

  • Shanshan Li & Kan-Yen Hsieh & Chiao-I Kuo & Tzu-Chi Lin & Szu-Hui Lee & Yi-Ru Chen & Chun-Hsiung Wang & Meng-Ru Ho & See-Yeun Ting & Kaiming Zhang & Chung-I Chang, 2023. "A 5+1 assemble-to-activate mechanism of the Lon proteolytic machine," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43035-2
    DOI: 10.1038/s41467-023-43035-2
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    References listed on IDEAS

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    1. Mia Shin & Edmond R. Watson & Albert S. Song & Jeffrey T. Mindrebo & Scott J. Novick & Patrick R. Griffin & R. Luke Wiseman & Gabriel C. Lander, 2021. "Structures of the human LONP1 protease reveal regulatory steps involved in protease activation," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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    Cited by:

    1. Xiaolong Zhao & Yongxiang Gao & Qingguo Gong & Kaiming Zhang & Shanshan Li, 2024. "Elucidating the Architectural dynamics of MuB filaments in bacteriophage Mu DNA transposition," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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