Regulation of the cell division hydrolase RipC by the FtsEX system in Mycobacterium tuberculosis

Jianwei Li, Xin Xu, Jian Shi, Juan A. Hermoso (), Lok-To Sham () and Min Luo ()
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Jianwei Li: National University of Singapore
Xin Xu: National University of Singapore
Jian Shi: National University of Singapore
Juan A. Hermoso: Consejo Superior de Investigaciones Científicas
Lok-To Sham: National University of Singapore
Min Luo: National University of Singapore

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The FtsEX complex regulates, directly or via a protein mediator depending on bacterial genera, peptidoglycan degradation for cell division. In mycobacteria and Gram-positive bacteria, the FtsEX system directly activates peptidoglycan-hydrolases by a mechanism that remains unclear. Here we report our investigation of Mycobacterium tuberculosis FtsEX as a non-canonical regulator with high basal ATPase activity. The cryo-EM structures of the FtsEX system alone and in complex with RipC, as well as the ATP-activated state, unveil detailed information on the signal transduction mechanism, leading to the activation of RipC. Our findings indicate that RipC is recognized through a “Match and Fit” mechanism, resulting in an asymmetric rearrangement of the extracellular domains of FtsX and a unique inclined binding mode of RipC. This study provides insights into the molecular mechanisms of FtsEX and RipC regulation in the context of a critical human pathogen, guiding the design of drugs targeting peptidoglycan remodeling.

Date: 2023
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DOI: 10.1038/s41467-023-43770-6

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