Authors
Melesse Nune, Anushya Petchiappan, Istvan Botos, Nadim Majdalani, Sydney H Shapiro, Rodolfo Ghirlando, Chin-Hsien Tai, Amila Abeykoon, Ann Marie Stanley, Bridgette M Beach, Susan Gottesman, Susan K Buchanan
Published in
bioRxiv : the preprint server for biology. May 09, 2026. Epub May 09, 2026.
Abstract
The Rcs phosphorelay regulates gene expression in response to cell envelope stress and is critical for the virulence of pathogenic bacteria, including Klebsiella pneumoniae, due to its regulation of genes related to extracellular capsule, cell division, and motility. The RcsC histidine kinase, RcsD phosphotransfer protein and RcsB response regulator, which form the core of the Rcs phosphorelay, are negatively regulated by the unique inner membrane protein IgaA via interaction with RcsD. An outer membrane lipoprotein, RcsF, activates signaling by interaction with IgaA, but the precise activation mechanisms remain unclear. In this study, we determined the structures of IgaA and the IgaA/RcsF complex using Cryo-electron microscopy (Cryo-EM). We also determined the structures of RcsC and RcsD, which both form homodimers stabilized by hydrophobic interactions, creating ladder-like structures. Combining the Cryo-EM structures, AlphaFold3 structure predictions of IgaA/RcsD and RcsF/IgaA/RcsD, and genetic studies, we describe a model for how RcsF modifies the IgaA/RcsD interaction, lifting negative regulation and activating the Rcs phosphorelay. Our findings provide a high-resolution depiction of the Rcs stress response system and suggest potential targets for small molecule inhibitors.
PMID:
42388801
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.
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