Abstract
The eukaryotic signal recognition particle (SRP) cotranslationally recognizes the first hydrophobic segment of nascent secretory and membrane proteins and delivers them to a receptor at the endoplasmic reticulum (ER). How substrates are released from SRP at the ER to subsequently access translocation factors is not well understood. We found that TMEM208 can engage the substrate binding domain of SRP to accelerate release of its bound cargo. Without TMEM208, slow cargo release resulted in excessive synthesis of downstream polypeptide before engaging translocation factors. Delayed access to translocation machinery caused progressive loss of insertion competence, particularly for multipass membrane proteins, resulting in their impaired biogenesis. Thus, TMEM208 facilitates prompt cargo handover from the targeting to translocation machinery to minimize biogenesis errors and maintain protein homeostasis.