Cotranslational signal-independent SRP preloading during membrane targeting

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Ribosome-associated factors must properly decode the limited information available in nascent polypeptides to direct them to their correct cellular fate1. It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site2,3. Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum, involving recognition of linear hydrophobic signal sequences or transmembrane domains by the signal recognition particle (SRP)4,5. Notably, the SRP has low abundance relative to the large number of ribosome–nascent-chain complexes (RNCs), yet it accurately selects those destined for the endoplasmic reticulum6. Despite their overlapping specificities, the SRP and the cotranslationally acting Hsp70 display precise mutually exclusive selectivityin vivofor their cognate RNCs7,8. To understand cotranslational nascent chain recognitionin vivo, here we investigate the cotranslational membrane-targeting cycle using ribosome profiling9in yeast cells coupled with biochemical fractionation of ribosome populations. We show that the SRP preferentially binds secretory RNCs before their targeting signals are translated. Non-coding mRNA elements can promote this signal-independent pre-recruitment of SRP. Our study defines the complex kinetic interaction between elongation in the cytosol and determinants in the polypeptide and mRNA that modulate SRP–substrate selection and membrane targeting.

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