Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 6, Pages 1899-1907Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000922
Keywords
positive charge; signal peptide; n-region; secretory preprotein; translocation; signal peptide; n-region; protein translocation; protein translocation; protein synthesis; protein translocation; protein domain; protein translocation; protein export; protein inport; protein processing; protein targeting
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Funding
- National Natural Science Foundation of China [81070629, 81570699, 81620108004, 81370895]
- National Institutes of Health [RO1-DK088856, RO1-DK-48280, R01-DK111174]
- Protein Folding Disease Initiative of the University of Michigan
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Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n-region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY.
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