Lipid activation of the signal recognition particle receptor provides spatial coordination of protein targeting

The highly conserved co‐translational protein targeting machinery comprised of the signal recognition particle (SRP) and its receptor (SR) is responsible for trafficking approximately one third of eukaryotic proteins and targeting membrane proteins to the inner membrane of prokaryotes. The bacterial SR, FtsY, has been shown to interact with anionic phospholipids of the plasma membrane. The mechanistic details of the FtsY‐phospholipid interaction and its effect on various stages of the SRP‐mediated protein targeting pathway remain unclear. Using solution‐ and surface‐based in vitro assays, we show that lipid binding activates FtsY, thus accelerating formation of a stable targeting complex with SRP and facilitating delivery of cargo proteins to the plasma membrane. Conversely, formation of the FtsY• SRP complex dramatically increases affinity of FtsY for phospholipids, leading to efficient partitioning of the targeting complex to the plasma membrane. Thus, phospholipids of the plasma membrane act as a spatial cue that facilitates efficient delivery of the cargo proteins to the translocation machinery. This work was supported by National Institutes of Health (NIH) grant GM078024, and career awards from the Burroughs Welcome Foundation, the Henry and Camille Dreyfus foundation, the Arnold and Mabel Beckman foundation, and the David and Lucile Packard foundation to S. Shan. D. Akopian and M. Rome were supported by NIH/National Research Service Award training grant 5T32GM07616.