Editing Protein targeting (section)

====== Mechanisms of transmembrane protein integration ======
Transmembrane proteins, which are partly integrated into the ER membrane rather than released into the ER lumen, have a complex assembly process.<ref name="Alberts-2018" /><ref name="Lodish-2008" /> The initial stages are similar to soluble proteins: a signal sequence starts the insertion into the ER membrane. However, this process is interrupted by a stop-transfer sequence—a string of hydrophobic amino acids—which causes the translocator to halt and release the protein laterally into the membrane.<ref name="Alberts-2018" /><ref name="Lodish-2008" /> This results in a single-pass transmembrane protein with one end inside the ER lumen and the other in the cytosol, and this orientation is permanent.<ref name="Alberts-2018" />

Some transmembrane proteins use an internal signal (start-transfer sequence) instead of one at the N-terminus, and unlike the initial signal sequence, this start-transfer sequence isn't removed.<ref name="Alberts-2018" /><ref name="Lodish-2008" /> It begins the transfer process, which continues until a stop-transfer sequence is encountered, at which point both sequences become anchored in the membrane as alpha-helical segments.<ref name="Alberts-2018" />

In more complex proteins that span the membrane multiple times, additional pairs of start- and stop-transfer sequences are used to weave the protein into the membrane in a fashion akin to a sewing machine. Each pair allows a new segment to cross the membrane and adds to the protein's structure, ensuring it is properly embedded with the correct arrangement of segments inside and outside the ER membrane.<ref name="Alberts-2018" />