How does the translocon differentiate between hydrophobic sequences that form part of either a GPI (glycosylphosphatidylinositol)-anchor signal or a stop transfer sequence?

Newly synthesized proteins entering the eukaryotic secretory pathway may be attached to the lipid membrane by essentially one of two mechanisms. They may either contain a hydrophobic stop transfer sequence that directs their integration into the bilayer with the consequence that the polypeptide spans the membrane either one or several times, or alternatively the polypeptide chain may be modified by the covalent addition of a lipid anchor resulting in the attachment of the protein to the membrane via the lipid moiety. The major pathway for the covalent addition of a lipid anchor involves the post-translational attachment of GPI (glycosylphosphatidylinositol) to the C-terminus. Proteins modified in this way contain a specific signal that is recognized by the GPI-anchor processing machinery. Hence both the integration of protein directly into the lipid bilayer and the addition of GPI anchors require the presence of sequences within the polypeptide chain to target the proteins to these pathways. This article will describe the main characteristics of these signals and their similarities and will discuss how the translocon may play a crucial role in their recognition.