Membrane protein targeting to the outskirts of the endoplasmic reticulum: A characterization of sorting signals

The majority of membrane proteins synthesized in the cell is inserted into the membrane of the endoplasmic reticulum (ER). The ER forms a network that extends from the nuclear envelope (NE), a double membrane surrounding the nucleus, to the cortical ER that underlies the plasma membrane (PM). Localization of membrane proteins to their destined membrane depends on the presence of sorting motifs. We investigated the transport of membrane proteins to the inner nuclear membrane (INM) of the NE and to regions where the ER membrane and PM are closely associated. Both targeting routes rely on a sorting motif composed of basic amino acids and an intrinsically disordered (ID) region between the transmembrane domain and the basic amino acids.
To reach the INM, membrane proteins have to travel through the nuclear pore complexes (NPCs) that form selective gates between the outer nuclear membrane and INM. For the transport route that we studied, the basic amino acids interact tightly with transport factors that are able to overcome the barrier of the NPC, while the ID region allows flexibility for the transport factors to interact properly with components of the NPC. In the targeting of membrane proteins to the PM-ER junctions the transmembrane domain of the protein remains in the ER, while the basic amino acids interact with the PM. Here, the ID region creates length to span the distance between the two membranes. For both localizations the ID region should be of sufficient length to mediate efficient targeting of the proteins.