The efficiency of protein compartmentalization into the secretory pathway.
Numerous proteins targeted for the secretory pathway are increasingly implicated in functional or pathological roles at alternative cellular destinations. The parameters that allow secretory or membrane proteins to reside in intracellular locales outside the secretory pathway remain largely unexplored. In this study, we have used an extremely sensitive and quantitative assay to measure the in vivo efficiency of signal sequence-mediated protein segregation into the secretory pathway. Our findings reveal that segregation efficiency varies tremendously among signals, ranging from >95 to <60%. The nonsegregated fraction is generated by a combination of mechanisms that includes inefficient signal-mediated translocation into the endoplasmic reticulum and leaky ribosomal scanning. The segregation efficiency of some, but not other signal sequences, could be influenced in cis by residues in the mature domain or in trans by yet unidentified cellular factors. These findings imply that protein compartmentalization can be modulated in a substrate-specific manner to generate biologically significant quantities of cytosolically available secretory and membrane proteins.
Levine
Corinna G
CG
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Mitra
Devarati
D
Sharma
Ajay
A
Smith
Carolyn L
CL
Hegde
Ramanujan S
RS
D020121:5' Untranslated Regions; D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism
D020121:5' Untranslated Regions; D008565:Membrane Proteins; D021382:Protein Sorting Signals; D011506:Proteins; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases