A new role for signal sequences: Regulation of protein biogenesis at the endoplasmic reticulum

The endoplasmic reticulum has evolved in eukaryotic cells in part to facilitate the sorting and processing of secretory and transmembrane proteins. These proteins are directed to the ER membrane by an interaction between a signal sequence and the signal recognition particle. Once at the membrane, the signal sequence of a nascent protein is recognized a second time by the translocation channel, which together with the associated proteins that regulate and influence translocation is known; as the translocon. Immediately after the onset of translocation the chain begins the complex process of folding, modification, and maturation in the ER lumen. As the first step in translocation, signal sequence recognition by the translocon has the potential to influence subsequent events of biogenesis, including integration, folding, and modification.;Analyzing early events in the trans location of model secretory proteins, we have found that the signal sequence of a nascent translocation substrate has the unexpected role of regulating the association between the ribosome and translocon. This role demands that signal sequences coevolve with their associated mature domains to effect proper regulation of the ribosome-translocon junction. The consequences of dysregulation of this step in biogenesis include a substantial translocation defect in the case of simple secretory proteins and the generation of altered topological forms in at least the case of prion protein biogenesis.;Studies on the maturation of secretory proteins have extended the role of the signal sequence to the regulation of protein maturation. We have found that signal sequence-translocon interactions dictate the pathway of maturation chosen by a nascent chain once its biogenesis has begun. Thus, the influence of a signal sequence can be manifested on a protein in the form of alterations in folding or modification long after the signal sequence itself has been removed.;Taken together, the work described here demonstrates that signal sequences have evolved a substrate-specific character to ensure the faithful biogenesis of secretory and transmembrane proteins.