Jiang Yeow, Kang Wei Tan, Daniel A. Holdbrook, Zhi-Soon Chong, Jan K. Marzinek, Peter J. Bond, and Shu-Sin Chng The architecture of the OmpC–MlaA complex sheds light on the maintenance of outer membrane lipid asymmetry in Escherichia coli J. Biol. Chem. 2018 293: 11325-. doi:10.1074/jbc.RA118.002441
Abstract:
A distinctive feature of the Gram-negative bacterial cell envelope is the asymmetric outer membrane (OM), where lipopolysaccharides and phospholipids (PLs) reside in the outer and inner leaflets, respectively. This unique lipid asymmetry renders the OM impermeable to external insults, including antibiotics and bile salts. In Escherichia coli, the complex comprising osmoporin OmpC and the OM lipoprotein MlaA is believed to maintain lipid asymmetry by removing mislocalized PLs from the outer leaflet of the OM. How this complex performs this function is unknown. Here, we defined the molecular architecture of the OmpC–MlaA complex to gain insights into its role in PL transport. Using in vivo photo-cross-linking and molecular dynamics simulations, we established that MlaA interacts extensively with OmpC and is located entirely within the lipid bilayer. In addition, MlaA forms a hydrophilic channel, likely enabling PL translocation across the OM. We further showed that flexibility in a hairpin loop adjacent to the channel is critical in modulating MlaA activity. Finally, we demonstrated that OmpC plays a functional role in maintaining OM lipid asymmetry together with MlaA. Our work offers glimpses into how the OmpC–MlaA complex transports PLs across the OM and has important implications for future antibacterial drug development.
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Funding Info:
This work was supported by funds from the National University of Singapore Graduate School for Integrative Sciences and Engineering scholarship (to J. Y.). Computational work was supported in part by the Singapore Ministry of Education Academic Research Fund Tier 3 Grant MOE2012-T3-1-008 (to J. K. M. and P. J. B.). All experimental work was supported by the National University of Singapore start-up funding and the Singapore Ministry of Education Academic Research Fund Tier 1 Grant and Tier 2 Grant MOE2013-T2-1-148 (to S.-S. C.).
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