Short hydrophobic sequences - an inhibitor of protein import into the ER

A large proportion of the proteome in mammals is transported via the endoplasmic reticulum (ER). For soluble proteins, this transport is triggered by an N-terminal signal sequence, whereupon the proteins pass the Sec61 channel and are imported into the ER. The signal sequence thus serves as a positive regulator for translocation and is generally sufficient for complete import, regardless of the mature part of the protein, with only a few known exceptions from this rule.
We discovered a formerly unknown negative regulator of the ER-import within the mature part of proteins. Soluble proteins possessing hydrophobic stretches with a length of around ten amino acids are imported incompletely into the ER despite carrying a signal sequence. Although many different types of proteins are able to pass the Sec61 channel, short hydrophobic sequences seem to be an obstacle to complete import. This suggests an evolutionary disadvantage for secretory proteins with short hydrophobic stretches. Work by Hessa et al. supports this theory, observing a lower local hydrophobicity in secretory proteins compared to proteins of the cytosol. Taken together, short hydrophobic sequences seem to serve as a negative regulator of the import into the ER via the Sec61 channel.