Specialized iNANO lecture: Structural studies of lipid flippases

Physical participation is subject to existing COVID-19 guidelines at the time of the lecture.

• Zoom link for the lecture (VPN required)

Assistant Professor Joseph A. Lyons

Department of Molecular Biology and Genetics, Aarhus University, Denmark

Structural studies of lipid flippases

Biological membranes are composed of bilayers, typically with highly asymmetric distributions of lipids that are of key importance for biomembrane function and dynamics, such as in secretory pathways, lipid signaling, cell-cell interactions, and motility. The asymmetric distributions are actively maintained by so-called lipid flippases and floppases that also counteract the passive scrambling of lipid gradients.  Dominating contributions in eukaryotes come from lipid flippases of the P4 subfamily of P-type ATPases. These transporters are involved in the inward active translocation, hence “flipping”, of phospholipids across the membrane bilayer. Central questions on P4 ATPase lipid flippases address i) their overall architecture and function in the take up and flipping of lipids in membranes, and ii) how they are able to accommodate and transport a much larger substrate than other P-type ATPases, which usually transport small cations. Additionally, some P4-ATPases are subjects to auto-inhibition mediated through extended cytosolic termini, a feature that is shared with other P-type ATPases, like the plasma membrane calcium ATPase.

To address these questions, we have studied the structure and function of yeast and mammalian phosphatidylserine specific lipid flippases. Single particle cryo-electron electron microscopy derived structures of the detergent solubilised yeast lipid flippase, Drs2p/Cdc50p, provide insights into protein auto-regulation and activation by a specific phosphatidylinositide-phosphate. In addition, structures of the bovine lipid flippase ATP8a2/CDC50A reconstituted in the membrane mimetic Salipro-nanoparticles, highlight the substrate lipid binding site, providing further insight into the transport mechanism.

Host: Acting Director Thomas Vosegaard