Having a NAC for nascent protein triage
The nascent polypeptide associated complex (NAC) is an abundant and conserved cotranslational chaperone that interacts with newly synthesized proteins on virtually every ribosome in eukaryotic cells. Many essential cellular functions have been attributed to NAC, including the de novo folding of nascent proteins, the biogenesis/maturation of ribosomes, as a ‘holdase’ chaperone for aggregation-prone proteins such as alpha-synuclein and polyQ, and as a proteostasis sensor. Leveraging our expertise in probing nascent protein interactions on the ribosome, we are beginning to test a new hypothesis: NAC is a molecular gatekeeper at the ribosome exit site that coordinates the recruitment of diverse protein biogenesis machineries and their correct pairing with nascent proteins, and thus ensuring the accurate selection of nascent proteins into their appropriate biogenesis pathways.
Mechanism of the NAC-SRP interplay on the ribosome to initiate ER targeting. NAC acts as “gatekeeper” to shield emerging nascent chains from non- physiological interactions with SRP. Because of its abundance and high affinity for the ribosome, NAC is bound to most riboomes at early stages of translation through a high-affinity anchor and a weakly bound globular domain that blocks SRP access to nascent polypeptides. The flexibly tethered UBA domain recruits SRP and increases its local concentration at the tunnel exit region to initiate sampling of nascent chains. The emergence of an ER signal sequence weakens the interactions of NAC’s globular domain with the ribosome. This allows SRP to bind the signal sequence at the exit of the ribosomal tunnel, displacing the globular domain of NAC. NAC remains associated with both the ribosome and SRP through the respective NACb anchor and UBA contacts until it reaches the ER membrane, where SR dis- places the UBA domain from SRP.