OZR back-up mandate: The role of transmembrane chaperones during outer membrane stress in Gram-negative bacteria

In Gram-negative bacteria the cytoplasmic membrane and peptidoglycan layer are surrounded by a second, “outer” membrane. With few exceptions, outer membrane integrity is critical to bacterial survival. In response to low Mg2+ concentrations, low pH and membrane destabilising antimicrobial peptides encountered during infection, the conserved PhoP/Q regulon induces modification of the outer membrane composition and the upregulation of various virulence pathways. We recently found that the SlyB lipoprotein, a core component of the PhoP/Q regulon, forms a transmembrane chaperone that takes up a vital role in the protection of outer membrane proteins from the destabilising effects of outer membrane modification and stress. The SlyB transmembrane domain is formed by a 2TM Glycine zipper, a domain of unknown function hitherto. Phylogenetic analysis, however, shows the 2TM Gly zipper domain is
widespread in Gram-negative bacteria, suggesting SlyB may represent a prototypical member of a larger family of transmembrane chaperones. In this project, I will perform a detailed molecular and structurefunction study of the conserved lipoprotein SlyB to determine its role in Gram-negative cell physiology, its interaction with client proteins and its regulatory network, and its position as a prototype member of a larger family of transmembrane chaperones.