Drs2 flips the phospholipid switch

The protein Drs2 flips phospholipids between membrane layers. Xu et al. identify which phospholipid the protein relocates to allow transport between the trans-Golgi network and the early endosome.

Drs2 commutes from the trans-Golgi network (TGN) to the early endosome (EE) and then back again. Without Drs2, cells can’t ship proteins along this route. The molecule is a flippase and moves phospholipids from the inner (lumenal) to the outer (cytosolic) leaflets of membranes. Insertion of a phospholipid into the cytosolic leaflet bends the membrane, which may help spur budding of new transport vesicles. Drs2 can flip the phospholipids phosphatidylserine and phosphatidylethanolamine, but researchers weren’t sure which proteins help Drs2 shift phospholipids and which type of phospholipid it moves to enable transport between the TGN and EEs.

Xu et al. revealed that Drs2 partners with the protein Gcs1, which is necessary for transport from the EE to the TGN, and lures Gcs1 to the EE and TGN. Gcs1 carries a motif, called ALPS, that recognizes bent membranes. However, the protein required a slightly longer version of the motif, which the team dubbed +ALPS, to attach to the EE and TGN. Transferring certain phospholipids into the outer leaflet not only bends the membrane, it also increases the negative charge on the surface. The lengthened ALPS sequence enables Gcs1 to recognize the bowed, negatively charged section of membrane created by Drs2.

By testing a mutant version of Drs2 that can’t grab phosphatidylserine but can attach to phosphatidylethanolamine, the team discovered that the protein relocates phosphatidylserine to promote transportation between the EE and TGN.