Molecular view of ER membrane remodeling by the Sec61/TRAP translocon

Protein translocation across the endoplasmic reticulum (ER) membrane is an essential initial step in protein entry into the secretory pathway. The conserved Sec61 protein translocon facilitates polypeptide translocation and coordinates cotranslational polypeptide processing events. In cells, the majority of Sec61 is stably associated with a heterotetrameric membrane protein complex, the translocon associated protein complex (TRAP), yet the mechanism by which TRAP assists in polypeptide translocation or cotranslational modifications such as N-glycosylation remains unknown. Here, we demonstrate the structure of the core Sec61/TRAP complex bound to a mammalian ribosome by Cryo-EM. The interactions with ribosome anchor the Sec61/TRAP complex in a conformation that renders the ER membrane locally thinner by significantly curving its the lumenal leaflet. We propose a model for how TRAP stabilizes the ribosome exit tunnel to assist nascent polypeptide insertion through Sec61 and provides a ratcheting mechanism into the ER lumen by direct polypeptide interactions.