A Ribosome-Associating Factor Chaperones Tail-Anchored Membrane Proteins

Hundreds of proteins are post-translationally inserted into the endoplasmic reticulum (ER) membrane by a single carboxy-terminal transmembrane domain (TMD)1. During targeting through the cytosol, the hydrophobic TMD of these tail-anchored (TA) proteins requires constant chaperoning to prevent aggregation or inappropriate interactions. A central component of this targeting system is TRC40, a conserved cytosolic factor that recognizes the TMD of TA proteins and delivers them to the ER for insertion2-4. The mechanism that permits TRC40 to effectively find and capture its TA protein cargos in a highly crowded cytosol is unknown. Here, we identify a conserved three-protein complex composed of Bat3, TRC35, and Ubl4A that facilitates TA protein capture by TRC40. This Bat3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the TMDs of newly released TA proteins, and transfers them to TRC40 for targeting. Depletion of the Bat3 complex allows non-TRC40 factors to compete for TA proteins, explaining their mislocalization in the analogous yeast deletion strains5-7. Thus, the Bat3 complex acts as a TMD selective chaperone that effectively channels TA proteins to the TRC40 insertion pathway.