Structural basis for maintenance of bacterial outer membrane lipid asymmetry

Nat Microbiol. 2017 Dec;2(12):1616-1623. doi: 10.1038/s41564-017-0046-x. Epub 2017 Oct 16.

Abstract

The Gram-negative bacterial outer membrane (OM) is a unique bilayer that forms an efficient permeation barrier to protect the cell from noxious compounds 1,2 . The defining characteristic of the OM is lipid asymmetry, with phospholipids comprising the inner leaflet and lipopolysaccharides comprising the outer leaflet 1-3 . This asymmetry is maintained by the Mla pathway, a six-component system that is widespread in Gram-negative bacteria and is thought to mediate retrograde transport of misplaced phospholipids from the outer leaflet of the OM to the cytoplasmic membrane 4 . The OM lipoprotein MlaA performs the first step in this process via an unknown mechanism that does not require external energy input. Here we show, using X-ray crystallography, molecular dynamics simulations and in vitro and in vivo functional assays, that MlaA is a monomeric α-helical OM protein that functions as a phospholipid translocation channel, forming a ~20-Å-thick doughnut embedded in the inner leaflet of the OM with a central, amphipathic pore. This architecture prevents access of inner leaflet phospholipids to the pore, but allows outer leaflet phospholipids to bind to a pronounced ridge surrounding the channel, followed by diffusion towards the periplasmic space. Enterobacterial MlaA proteins form stable complexes with OmpF/C 5,6 , but the porins do not appear to play an active role in phospholipid transport. MlaA represents a lipid transport protein that selectively removes outer leaflet phospholipids to help maintain the essential barrier function of the bacterial OM.

MeSH terms

  • Bacteria / chemistry*
  • Bacteria / metabolism
  • Bacterial Outer Membrane Proteins / chemistry*
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / metabolism
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Biological Transport
  • Cell Membrane / chemistry*
  • Crystallography, X-Ray
  • DNA, Bacterial / genetics
  • Diffusion
  • Genetic Vectors
  • Gram-Negative Bacteria / chemistry
  • Gram-Negative Bacteria / metabolism
  • Lipid Bilayers
  • Lipopolysaccharides / chemistry
  • Membrane Lipids / chemistry*
  • Molecular Dynamics Simulation
  • Mutation
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Porins / chemistry
  • Protein Conformation

Substances

  • Bacterial Outer Membrane Proteins
  • Bacterial Proteins
  • DNA, Bacterial
  • Lipid Bilayers
  • Lipopolysaccharides
  • Membrane Lipids
  • OmpC protein
  • OmpF protein
  • Phospholipids
  • Porins