RT Journal Article
SR Electronic
T1 Substrate Transport and Specificity in a Phospholipid Flippase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.24.169771
DO 10.1101/2020.06.24.169771
A1 Yong Wang
A1 Joseph A Lyons
A1 Milena Timcenko
A1 Felix Kümmerer
A1 Bert L. de Groot
A1 Poul Nissen
A1 Vytautas Gapsys
A1 Kresten Lindorff-Larsen
YR 2021
UL http://biorxiv.org/content/early/2021/08/27/2020.06.24.169771.abstract
AB Type 4 P-type ATPases are lipid flippases which help maintain asymmetric phospholipid distribution in eukaryotic membranes by driving unidirectional translocation of phospholipid substrates. Recent cryo-EM and crystal structures have provided a detailed view of flippases, and we here use molecular dynamics simulations to study the first steps of phospholipid transport and lipid substrate specificity. Our simulations and new cryo-EM structure shows phospholipid binding to a groove and subsequent movement towards the centre of the membrane, and reveal a preference for phosphatidylserine lipids. We find that only the lipid head group stays in the groove while the lipid tails remain in the membrane, thus visualizing how flippases have evolved to transport large substrates. The flippase also induces deformation and thinning of the outer leaflet facilitating lipid recruitment. Our simulations provide insight into substrate binding to flippases and suggest that multiple sites and steps in the functional cycle contribute to substrate selectivity.Competing Interest StatementThe authors have declared no competing interest.