The membrane-cytoplasmic linker defines activity of FtsH proteases inPseudomonas aeruginosaclone C

Author:

Mawla Gina DORCID,Mansour Kamal ShadyORCID,Cao Lianying,Purhonen Pasi,Hebert HansORCID,Sauer Robert TORCID,Baker Tania AORCID,Römling UteORCID

Abstract

AbstractPandemicPseudomonas aeruginosaclone C strains encode a xenolog of FtsH (PaFtsH2), an inner-membrane associated ATP-dependent protease.FtsH1supports growth and intrinsic antibiotic resistance but cannot be replaced byftsH2. We show that purified PaFtsH2 degrades fewer substrates than PaFtsH1. Swapping residues of a short MC peptide that links transmembrane helix-2 with the cytosolic AAA+ ATPase module from PaFtsH1 into PaFtsH2 improves hybrid-enzyme substrate processingin vitroand enables PaFtsH2 to substitute for PaFtsH1in vivo. FtsH1 MC peptides are glycine rich. Introducing three glycines into the membrane-proximal end of PaFtsH2’s MC linker is sufficient to elevate activityin vitroandin vivo. Electron microscopy including PaFtsH2 indicates that MC linker identity influences FtsH flexibility. Our findings establish that the efficiency of substrate processing by two PaFtsH isoforms depends on how they are attached to the membrane and suggest that greater linker flexibility/length allows FtsH to degrade a wider spectrum of substrates. As FtsH2 homologs occur across bacterial phyla, we hypothesize that FtsH2 is not a latent enzyme, rather recognizes specific substrates or is activated in specific contexts or biological niches. We hypothesize that such linkers might play a more determinative role in functionality and physiological impact of FtsH proteases than previously thought.

Publisher

Cold Spring Harbor Laboratory

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