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MBC in Press, published online ahead of print September 27, 2006
Mol. Biol. Cell 10.1091/mbc.E06-07-0626

A more recent version of this article appeared on December 1, 2006
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Submitted on July 24, 2006
Revised on September 14, 2006
Accepted on September 20, 2006

Not All Secretory Granules Are Created Equal: Partitioning of Soluble Content Proteins

Jacqueline A. Sobota,* Francesco Ferraro,* Nils Bäck,{dagger} Betty A. Eipper,* and Richard E. Mains*

*Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030-3401; {dagger}Department of Anatomy, Institute of Biomedicine, University of Helsinki, FIN-00014, Helsinki, Finland

Monitoring Editor: Randy Schekman

Secretory granules carrying fluorescent cargo proteins are widely used to study granule biogenesis, maturation, and regulated exocytosis. We fused the soluble secretory protein peptidylglycine {alpha}-hydroxylating monooxygenase (PHM) to green fluorescent protein (GFP) to study granule formation. When expressed in AtT-20 or GH3 cells, the PHM-GFP fusion protein partitioned from endogenous hormone (adrenocorticotropic hormone, growth hormone) into separate secretory granule pools. Both exogenous and endogenous granule proteins were stored and released in response to secretagogue. Importantly, we found that segregation of content proteins is not an artifact of overexpression nor peculiar to GFP-tagged proteins. Neither luminal acidification nor cholesterol-rich membrane microdomains play essential roles in soluble content protein segregation. Our data suggest that intrinsic biophysical properties of cargo proteins govern their differential sorting, with segregation occurring during the process of granule maturation. Proteins that can self-aggregate are likely to partition into separate granules, which can accommodate only a few thousand copies of any content protein; proteins that lack tertiary structure are more likely to distribute homogeneously into secretory granules. Therefore, a simple "self-aggregation default" theory may explain the little acknowledged, but commonly observed, tendency for both naturally occurring and exogenous content proteins to segregate from each other into distinct secretory granules.

Address correspondence to: Richard E. Mains (mains{at}uchc.edu)




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