Abstract
The Gram-negative outer-membrane envelops the bacterium and functions as a permeability barrier against antibiotics, detergents, and environmental stresses. Some virulence factors serve to maintain the integrity of the outer membrane, including DolP (formerly YraP) a protein of unresolved structure and function. Here, we reveal DolP is a lipoprotein functionally conserved amongst Gram-negative bacteria and that loss of DolP increases membrane fluidity. We present the NMR solution structure for Escherichia coli DolP, which is composed of two BON domains that form an interconnected opposing pair. The C-terminal BON domain binds anionic phospholipids through an extensive membrane:protein interface. This interaction is essential for DolP function and is required for sub-cellular localisation of the protein to the cell division site, providing evidence of subcellular localisation of these phospholipids within the outer membrane. The structure of DolP provides a new target for developing therapies that disrupt the integrity of the bacterial cell envelope.
Highlights
Gram-negative bacteria are intrinsically resistant to many antibiotics and environmental insults, which is largely due to the presence of their hydrophobic outer membrane (OM)
Bioinformatic analyses predicted that dolP encodes a lipoprotein with two putative domains of unknown function, termed BON domains (Yeats and Bateman, 2003), as well as a Lol-dependent OM targeting signal sequence where acylation was predicted to occur on cysteine residue C19
We have revealed the first structure of a dual-BON-domain protein, a protein architecture that is widely conserved amongst bacteria and provides insight into a diverse range of proteins acting in different organisms
Summary
Gram-negative bacteria are intrinsically resistant to many antibiotics and environmental insults, which is largely due to the presence of their hydrophobic outer membrane (OM). This asymmetric bilayer shields the periplasmic space, a thin layer of peptidoglycan and the inner membrane (IM). In the model bacterium Escherichia coli, the IM is a symmetrical phospholipid bilayer, whereas the OM has a more complex organisation with lipopolysaccharide (LPS) and phospholipids forming an Bryant, Morris, Knowles, et al eLife 2020;9:e62614. The growth of all three envelope layers must be tightly coordinated in order to maintain membrane integrity. Improper coordination can lead to bacterial growth defects, sensitivity to antibiotics, and can cause cell lysis (Egan, 2018; Gray et al, 2015)
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