LAUSR

The nascent polypeptide–associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC’s globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization. Description NAC acts as a gatekeeper on the ribosome In eukaryotes, signal recognition particle (SRP) targets membrane and secretory proteins to the endoplasmic reticulum (ER) while they are being synthesized on the ribosome. To prevent erroneous targeting of proteins to the ER, access of SRP is regulated by the nascent polypeptide–associated complex (NAC). Jomaa et al. investigated how NAC can prevent SRP from binding ribosomes that are synthesizing cytosolic and mitochondrial proteins while at the same time recruiting SRP to ribosomes translating an ER protein client. Their findings reveal the role of NAC as a key sorting factor for nascent chains that helps to ensure the specificity of membrane and secretory protein localization in eukaryotes. —SMH The nascent polypeptide–associated complex regulates signal recognition particle function and controls endoplasmic reticulum targeting.