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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.

2025-10-04 biochemistry
10.1101/2025.10.03.679995 bioRxiv
Show 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.

Published in ACS Chemical Biology · training set

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