LAUSR

When do you really need SRP? Proteins destined for the cell exterior are recruited during synthesis to the surface of the endoplasmic reticulum (ER) by the signal recognition particle (SRP). The classic view suggests that SRP recognizes signal sequences at the beginning of proteins. Working in yeast, Costa et al. found that many proteins with cleavable signal peptides were efficiently targeted during synthesis in the absence of SRP. In contrast, proteins with internal targeting signals universally depended on SRP and were susceptible to aberrant mitochondrial targeting in its absence. These studies establish the full physiological role of SRP in ensuring accurate and efficient protein targeting in the secretory pathway. Science, this issue p. 689 The signal recognition particle prevents protein mistargeting to mitochondria and is not universally required for cotranslational targeting to the yeast endoplasmic reticulum. The signal recognition particle (SRP) enables cotranslational delivery of proteins for translocation into the endoplasmic reticulum (ER), but its full in vivo role remains incompletely explored. We combined rapid auxin-induced SRP degradation with proximity-specific ribosome profiling to define SRP’s in vivo function in yeast. Despite the classic view that SRP recognizes amino-terminal signal sequences, we show that SRP was generally essential for targeting transmembrane domains regardless of their position relative to the amino terminus. By contrast, many proteins containing cleavable amino-terminal signal peptides were efficiently cotranslationally targeted in SRP’s absence. We also reveal an unanticipated consequence of SRP loss: Transcripts normally targeted to the ER were mistargeted to mitochondria, leading to mitochondrial defects. These results elucidate SRP’s essential roles in maintaining the efficiency and specificity of protein targeting.