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MBC in Press, published online ahead of print October 20, 2004
Mol. Biol. Cell 10.1091/mbc.E04-06-0508

A more recent version of this article appeared on January 1, 2005
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Submitted on June 22, 2004
Revised on September 21, 2004
Accepted on October 5, 2004

The Efficiency of Protein Compartmentalization into the Secretory Pathway

Corinna G. Levine,* Devarati Mitra,* Ajay Sharma,* Carolyn L. Smith,{dagger} and Ramanujan S. Hegde*{ddagger}

*Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; {dagger}Light Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Monitoring Editor: Reid Gilmore

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 utilized 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 more than 95% to <60%. The nonsegregated fraction is generated by a combination of mechanisms that includes inefficient signal-mediated translocation into the ER 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.

{ddagger}Corresponding author. E-mail: hegder{at}mail.nih.gov






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