Protein translocation across the endoplasmic reticulum (ER) membrane is triggered at several stages by information contained in the signal sequence. Initially, the signal sequence of a nascent secretory protein upon emergence from the ribosome is recognized by a polypeptide of relative molecular mass 54,000 (M r 54K) which is part of the signal recognition particle (SRP)1,2,27. Binding of SRP may induce a site-specific elongation arrest of translation in vitro 1,3. Attachment of the arrested translation complex to the ER membrane is mediated by the SRP-receptor (docking protein)3,4 and is accompanied by displacement of the SRP from both the ribosome5 and the signal sequence6. We have investigated the fate of the signal sequence following the disengagement of SRP and its receptor by a crosslinking approach2,6. We report here that the signal sequence of nascent preprolactin, after its release from the SRP, interacts with a newly discovered component, a signal sequence receptor (SSR), which is an integral, glycosylated pmrotein of the rough ER membrane (M r∼35K).