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bioRxiv · 10.1101/2025.10.03.679995

Cryo-EM structure of the FtsH periplasmic domain reveals functional dynamics

Goc, G.·Yadav, S. K. N.·Orriss, G.·Borucu, U.·Berger, I.·Schaffitzel, C.·Kabasakal, B. V.
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Abstract

FtsH, an essential AAA+ metalloprotease, maintains cellular homeostasis by degrading misfolded and membrane-associated proteins. Here, we report cryo-EM structures of the Escherichia coli FtsH periplasmic domain (FtsH-PD) revealing insights into its conformational flexibility. Initial 2D class averages suggested three distinct orientations, right-handed and left-handed maps of FtsH-PD, and a map with a different conformation. The 4.9 [A] structure of FtsH-PD exhibits the conserved +{beta} fold, while the 7.3 [A] map with the different conformation displays a 20{o} clockwise rotation of two alpha helices. These findings support a model where conformational changes are present not only in the FtsH cytosolic domain, but also in the periplasmic domain and potentially facilitate substrate translocation through a combination of mechanisms involving both the FtsH-PD and the HflKC complexed with FtsH, along with lipid-scramblase activity to assist in membrane protein extraction. This study points out novel perspectives on how conformational changes in the periplasmic domain contribute to FtsH substrate degradation mechanisms.

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Goc, G., Yadav, S. K. N., Orriss, G., Borucu, U., Berger, I., Schaffitzel, C., Kabasakal, B. V.. 2025-10-04. Cryo-EM structure of the FtsH periplasmic domain reveals functional dynamics. https://doi.org/10.1101/2025.10.03.679995

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