Mechanism of P4-ATPase catalyzed lipid transport

P4-ATPases are lipid-transporting proteins belonging to the superfamily of P-type ATPases, a group of integral membrane pumps mainly involved in cation transport. Although P4-ATPases present high sequence similarity to other members of the P-type family, they also show remarkable differences, especially with respect to the amino acid residues involved in substrate binding.

Although this may suggest an adaptation to accomplish lipid translocation, it is not known how these proteins are able to move such large molecules as the phospholipids from one side of the membrane to the other.

Our research questions are: How are lipids transported by P4-ATPases? Which amino acid residues are involved in lipid binding? Do phospholipids get fully embedded in a central pocket in the structure of P4-ATPases or do the fatty acid chains stay out of the protein and always in contact with the hydrophobic bilayer?

We are aiming at answering these questions through a range of biochemical and biophysical approaches.

Models for lipid transport by a P4-ATPase: A) Do lipids enter a central pocket in the P4-ATPases, as transported cations do in other P-type ATPases? B) Is the lipid headgroup sliding along a lateral surface in the P4-ATPase with the fatty acid chains always in contact with the hydrophobic bilayer?


Selected publications

  • López-Marqués RL, Poulsen LR, Bailly A, Geisler M, Pomorski TG, Palmgren MG. Structure and mechanism of ATP-dependent phospholipid transporters, Biochim Biophys Acta 1850 (2015), 461-475.
  • Theorin L, Faxén K, Sørensen DM, Migotti R, Dittmar G, Schiller J, Daleke DL, Palmgren M, López-Marqués RL, Günther Pomorski T. The lipid head group is the key element for substrate recognition by the P4 ATPase ALA2: a phosphatidylserine flippase. Biochem J., 476 (2019) 783-794.
  • Jensen MS, Costa SR, Duelli AS, Andersen PA, Poulsen LR, Stanchev LD, Gourdon P, Palmgren M Günther Pomorski T, López-Marqués RL. Phospholipid flipping involves a central cavity in P4 ATPases. Sci Rep., 7 (2017) 17621