Positive Charge in the n‐region of the Signal Peptide Contributes to Efficient Post‐translational Translocation of Small Secretory Proteins

Abstract

A majority of secretory proteins in mammalian cells undergo signal recognition particle (SRP) dependent co‐translationally translocation across the endoplasmic reticulum (ER). However, due to minimal time for SRP recognition, many small secretory proteins can be post‐translationally tanslocated into the ER. Several chaperones and cellular machinery have been identified to be involved in post‐translational translocation of these small secretory proteins. However, the intrinsic signals of small secretory proteins that contribute to efficient post‐translational translocation remain unknown. Here, we analyzed signal sequences of eukaryotic secretory proteins and found that the percentage of the proteins with positive charge in the n‐region of their signal peptide (SP) increases substantially as the polypeptides become shorter. Eliminating the n‐region positive charge selectively impaired translocation of small secretory proteins. This translocation impairment appeared to be mainly caused by the defect of post‐translational translocation. Slowing down protein translational rate of small secretory proteins could alleviate their translocation defects caused by loss of SP N‐terminal positive charge. Together, these data revealed a previously unrecognized role of n‐region positive charge in ensuring efficiency of post‐translational translocation of small secretory proteins.Support or Funding InformationThis work was supported by NIH RO1‐DK088856, and by the research grants from The National Natural Science Foundation of China 81070629, 81370895, 81570699.