A ribosome-associating factor chaperones tail-anchored membrane proteins

Abstract

Tail-anchored (TA) proteins have a single transmembrane domain at their C-termini and are post-translationally targeted to the endoplasmic reticulum via the cytosolic ATPase, TRC40. In this study, Mariappan et al. identify a conserved protein complex called Bat3 complex that is recruited to ribosomes and interacts with the transmembrane domain of newly released TA proteins, transferring them to TRC40 for subsequent targeting to the endoplasmic reticulum. Thus the Bat3 complex functions as a transmembrane-domain-specific chaperone that channels TA proteins to the TRC40 insertion pathway. Tail-anchored proteins have a single transmembrane domain at their carboxy termini and are post-translationally targeted to the endoplasmic reticulum via the cytosolic ATPase TRC40. These authors identify a conserved protein complex called Bat3 complex that is recruited to ribosomes, interacts with the transmembrane domain of newly released tail-anchored proteins and transfers them to TRC40 for subsequent targeting to the endoplasmic reticulum. Hundreds of proteins are inserted post-translationally 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 insertion2,3,4. The mechanism that permits TRC40 to find and capture its TA protein cargos effectively 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 strains5,6,7. Thus, the Bat3 complex acts as a TMD-selective chaperone that effectively channels TA proteins to the TRC40 insertion pathway.