Project 03

Molecular basis of lipid transport across the periplasm

Principle Investigator: Prof. Dr. Klaas Martinus Pos

Research Areas: Membrane, Biochemistry, Structural Biology

Summary

The periplasm of Gram-negative bacteria is confined by the inner membrane (IM) composed of a bilayer of phospholipids and the outer membrane (OM), with an inner layer of phospholipids and an outer layer of mainly lipopolysaccharides. The preservation of the OM-lipid asymmetry is necessary to protect the cell from hydrophobic toxins. In Campylobacter jejuni  the transport of phospholipids between the IM and OM is presumably based on lipid shuttling catalyzed by an RND transporter and MlaA/MlaC homologs. In project P03, we will investigate the role of the putative lipid RND transporter, its dependence on MlaA and MlaC homologs, its structure, function, and the molecular mechanism of lipid transport through the periplasm.

Prof. Dr. Klaas Martinus Pos

Institute of Biochemistry Goethe University, Frankfurt

Website

P03: PROJECT-RELATED PUBLICATIONS

  1. Plé C#, Tam HK#, Vieira Da Cruz A, Compagne N, Jiménez-Castellanos JC, Müller RT, Pradel E, Foong WE, Malloci G, Ballée A, Kirchner MA, Moshfegh P, Herledan A, Herrmann A, Déprez B, Willand N, Vargiu AV, Pos KM*, Flipo M*, Hartkoorn RC* (2022) A new and potent family of allosteric inhibitors of RND-type multidrug efflux pumps. Nat. Commun. 13: 115
  2. Ornik-Cha A#, Wilhelm J#, Kobylka J, Sjuts H, Vargiu AV, Malloci G, Reitz J, Seybert A, Frangakis AS*, Pos KM* (2021) Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms. Nat. Commun. 12: 6919
  3. Tam HK, Foong WE, Oswald C, Herrmann A, Zeng H, Pos KM* (2021) Allosteric drug transport mechanism of multidrug transporter AcrB. Nat. Commun. 12: 3889
  4. Alav I, Kobylka J, Kuth MS, Pos KM, Picard M., Blair JMA, Bavro VN. (2021) Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria. Chem. Rev. 121: 5479-5596
  5. Yousefian N, Ornik-Cha A, Poussard S, Decossas M, Berbon M, Daury L, Taveau JC, Dupuy J, Đorđević-Marquardt S, Lambert O*, Pos KM* (2021) Structural characterization of the EmrAB-TolC efflux complex from E. coli. Biochim Biophys Acta – Biomembr. 1863: 183488
  1. Tam HK, Malviya VN, Foong WE, Herrmann A, Malloci G, Ruggerone P, Vargiu AV*, Pos KM* (2020) Binding and transport of carboxylated drugs by the multidrug transporter AcrB. J Mol Biol 432: 861-877
  2. Müller RT, Travers T, Cha HJ, Phillips J L, Gnanakaran S, Pos KM* (2017) Switch loop flexibility affects substrate transport of the AcrB efflux pump. J Mol Biol 429: 3863-74
  3. Masi M, Réfregiers M, Pos KM, Pagès J-M (2017) Mechanisms of envelope permeability and antibiotic influx and efflux in Gram-negative bacteria. Nat Microbiol 2: 17001
  4. Oswald C, Tam H-K, Pos KM (2016) Transport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB. Nat Commun 7: 13819
  5. Sjuts H, Vargiu AV*, Kwasny SM, Nguyen ST, Kim H-S, Ding X, Ornik AR, Ruggerone P, Bowlin T, Nikaido H*, Pos KM*, Opperman TJ* (2016) Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proc Nat Acad Sci USA 113: 3509-14
# equally contributed *corresponding author