The distributions of proteins with a long (red) and short (green) transmembrane domain don't overlap.

Acell uses a simple trick to keep certain proteins from leaving the ER: it bars them from the organelle's exits. Ronchi et al. show how cells determine which proteins to keep out.

Proteins due to be exported from the cell enter the ER, where they get bundled into vesicles that spirit them to the Golgi apparatus. One way that the ER prevents its resident proteins from departing by the same route is to exclude them from exit sites. But researchers didn't know what characteristics get a protein banished. Ronchi et al. suspected that the ER sorts proteins by their transmembrane domain (TMD).

To test the idea, the researchers altered human cells to manufacture two proteins that were identical except for their TMD, which was 22 amino acids long in one molecule and 17 in the other. The team had previously shown that the longer protein leaves the ER, while the shorter one stays behind. The new work shows that the 17–amino acid protein tended to avoid the ER exit sites. The longer protein, however, moved into and out of the sites, and a small amount of it accumulated there.

Where each protein ends up might depend on which lipids it associates with, the researchers speculate. Because its TMD is longer and more hydrophobic, the 22–amino acid version might seek stiffer lipid domains, which could gather at the exit sites. The shorter protein, by contrast, would fit in better with less orderly, thinner portions of the membrane.


Ronchi, P., et al.
J. Cell Biol.