Editing Protein targeting (section)

==== Protein synthesis and sorting  ====
There are two types of proteins that move to the ER: water-soluble proteins, which completely cross into the ER lumen, and transmembrane proteins, which partly cross and embed themselves within the ER membrane.<ref name="Lodish-2008" /> These proteins find their way to the ER with the help of an ER signal sequence, a short stretch of hydrophobic amino acids.<ref name="Alberts-2018" />

Proteins entering the ER are synthesized by ribosomes. There are two sets of ribosomes in the cell: those bound to the ER (making it look 'rough') and those floating freely in the cytosol. Both sets are identical but differ in the proteins they synthesize at a given moment.<ref name="Alberts-2018" /><ref name="Lodish-2008" /> Ribosomes that are making proteins with an ER signal sequence attach to the ER membrane and start the translocation process. This process is energy-efficient because the growing protein chain itself pushes through the ER membrane as it elongates.<ref name="Alberts-2018" />

As the mRNA is translated into a protein, multiple ribosomes may attach to it, creating a structure called a polyribosome.<ref name="Alberts-2018" /> If the mRNA is coding for a protein with an ER signal sequence, the polyribosome attaches to the ER membrane, and the protein begins to enter the ER while it is still being synthesized.<ref name="Lodish-2008" /><ref name="Alberts-2018" />

===== Guided entry of soluble proteins =====
In the process of protein synthesis within eukaryotic cells, soluble proteins that are destined for the endoplasmic reticulum (ER) or for secretion out of the cell are guided to the ER by a two-part system. Firstly, a signal-recognition particle (SRP) in the cytosol attaches to the emerging protein's ER signal sequence and the ribosome itself.<ref name="Alberts-2018" /> Secondly, an SRP receptor located in the ER membrane recognizes and binds to the SRP. This interaction temporarily slows down protein synthesis until the SRP and ribs complex binds to the SRP receptor on the ER.<ref name="Alberts-2018" /><ref name="Lodish-2008" />

Once this binding occurs, the SRP is released, and the ribosome is transferred to a protein translocator in the ER membrane, allowing protein synthesis to continue.<ref name="Alberts-2018" /><ref name="Lodish-2008" /> The polypeptide chain of the protein is then threaded through a channel in the translocator into the ER lumen. The signal sequence of the protein, typically at the beginning (N-terminus) of the polypeptide chain, plays a dual role. It not only targets the ribosome to the ER but also triggers the opening of the translocator.<ref name="Alberts-2018" /> As the protein is fed through the translocator, the signal sequence stays attached, allowing the rest of the protein to move through as a loop. A signal peptidase inside the ER then cuts off the signal sequence, which is subsequently discarded into the lipid bilayer of the ER membrane and broken down.<ref name="Alberts-2018" /><ref name="Lodish-2008" />

Finally, once the last part of the protein (the C-terminus) passes through the translocator, the entire soluble protein is released into the ER lumen, where it can then fold and undergo further modifications or be transported to its final destination.<ref name="Alberts-2018" /><ref name="Lodish-2008" />

====== 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" />