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

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 () and Chung-I Chang ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43035-2

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