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Cryo-EM Structure of the Periplasmic Domain of AAA Protease FtsH
Structural highlights
FunctionFTSH_ECOLI Acts as a processive, ATP-dependent zinc metallopeptidase for both cytoplasmic and membrane proteins. Plays a role in the quality control of integral membrane proteins. Degrades a few membrane proteins that have not been assembled into complexes such as SecY, F(0) ATPase subunit a and YccA, and also cytoplasmic proteins sigma-32, LpxC, KdtA and phage lambda cII protein among others. Degrades membrane proteins in a processive manner starting at either the N- or C-terminus; recognition requires a cytoplasmic tail of about 20 residues with no apparent sequence requirements. It presumably dislocates membrane-spanning and periplasmic segments of the protein into the cytoplasm to degrade them, this probably requires ATP. Degrades C-terminal-tagged cytoplasmic proteins which are tagged with an 11-amino-acid nonpolar destabilizing tail via a mechanism involving the 10SA (SsrA) stable RNA.[1] [2] [3] [4] As FtsH regulates the levels of both LpxC and KdtA it is required for synthesis of both the protein and lipid components of lipopolysaccharide (LPS).[5] [6] [7] [8] Publication Abstract from PubMedFtsH, an AAA + metalloprotease that is essential in bacteria and eukaryotic organelles, 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 intrinsic conformational flexibility. Our analysis resolved two distinct states: a 4.9 A structure exhibiting the conserved alpha + beta fold and a 7.3 A map representing distinct rotated-helix conformation characterized by 20 degrees 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. This flexibility potentially facilitates 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 offers new perspectives on how conformational changes in the periplasmic domain contribute to FtsH substrate degradation mechanisms. Cryo-EM Structure of the FtsH Periplasmic Domain Reveals Functional Dynamics.,Goc G, Yadav SKN, Orriss G, Borucu U, Berger I, Schaffitzel C, Kabasakal BV ACS Chem Biol. 2026 Apr 17;21(4):844-851. doi: 10.1021/acschembio.5c01025. Epub , 2026 Apr 7. PMID:41944809[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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