LptM promotes oxidative maturation of the lipopolysaccharide translocon by substrate binding mimicry

• Published in: Nature communications 2023-10, Vol.14 (1), p.6368-6368, Article 6368
• Main Authors: Yang, Yiying, Chen, Haoxiang, Corey, Robin A., Morales, Violette, Quentin, Yves, Froment, Carine, Caumont-Sarcos, Anne, Albenne, Cécile, Burlet-Schiltz, Odile, Ranava, David, Stansfeld, Phillip J., Marcoux, Julien, Ieva, Raffaele
• Format: Article
• Language: English
• Subjects: 101/58; 38/1; 631/326/88; 631/57/2266; 631/92/314; 82/51; 82/80; 82/83; Bacterial Outer Membrane Proteins - metabolism; Binding; Biochemical analysis; Cell Membrane - metabolism; Chemical bonds; Disulfide bonds; Disulfides - metabolism; E coli; Escherichia coli; Escherichia coli - genetics; Escherichia coli - metabolism; Escherichia coli Proteins - chemistry; Humanities and Social Sciences; Inactivation; Insertion; Isomerization; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lipoproteins - metabolism; Maturation; Membrane proteins; Membranes; Mimicry; multidisciplinary; Oxidative Stress; Science; Science (multidisciplinary); Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42007-w

Insertion of lipopolysaccharide (LPS) into the bacterial outer membrane (OM) is mediated by a druggable OM translocon consisting of a β-barrel membrane protein, LptD, and a lipoprotein, LptE. The β-barrel assembly machinery (BAM) assembles LptD together with LptE at the OM. In the enterobacterium Escherichia coli , formation of two native disulfide bonds in LptD controls translocon activation. Here we report the discovery of LptM (formerly YifL), a lipoprotein conserved in Enterobacteriaceae , that assembles together with LptD and LptE at the BAM complex. LptM stabilizes a conformation of LptD that can efficiently acquire native disulfide bonds, whereas its inactivation makes disulfide bond isomerization by DsbC become essential for viability. Our structural prediction and biochemical analyses indicate that LptM binds to sites in both LptD and LptE that are proposed to coordinate LPS insertion into the OM. These results suggest that, by mimicking LPS binding, LptM facilitates oxidative maturation of LptD, thereby activating the LPS translocon. Here, the authors identify a third component of the outer membrane LPS translocon in Escherichia coli called LptM. Biochemical analysis and structural modelling reveal that LptM binds the LPS translocon by mimicking its native substrate, so stabilising an active conformation of the complex.