Different proteins need to be sent to different parts of a eukaryotic cell, or, in some cases, exported out of the cell and into the extracellular space. How do the right proteins get to the right places?
Cells have various shipping systems, kind of like molecular versions of the postal service, to make sure that proteins arrive at their correct destinations. In these systems, molecular labels (often, amino acid sequences) are used to "address" proteins for delivery to specific locations. Let’s take a look at how these shipping systems work.
Overview of cellular shipping routes
Translation of all proteins in a eukaryotic cell begins in the cytosol (except for a few proteins made in mitochondria and chloroplasts). As a protein is made, it passes step by step through a shipping "decision tree." At each stage, the protein is checked for molecular tags to see if it needs to be re-routed to a different pathway or destination.
Diagram based on similar diagram in Alberts et al.
The first major branch point comes shortly after translation starts. At this point, the protein will either remain in the cytosol for the rest of translation, or be fed into the endoplasmic reticulum (ER) as it is translated.
- Proteins are fed into the ER during translation if they have an amino sequence called a signal peptide. In general, proteins bound for organelles in the endomembrane system (such as the ER, Golgi apparatus, and lysosome) or for the exterior of the cell must enter the ER at this stage.
- Proteins that do not have a signal peptide stay in the cytosol for the rest of translation. If they lack other "address labels," they'll stay in the cytosol permanently. However, if they have the right labels, they can be sent to the mitochondria, chloroplasts, peroxisomes, or nucleus after translation.
The endomembrane system and secretory pathway
Proteins destined for any part of the endomembrane system (or the outside of the cell) are brought to the ER during translation and fed in as they're made.
Signal peptides
The signal peptide that sends a protein into the endoplasmic reticulum during translation is a series of hydrophobic (“water-fearing”) amino acids, usually found near the beginning (N-terminus) of the protein. When this sequence sticks out of the ribosome, it’s recognized by a protein complex called the signal-recognition particle (SRP), which takes the ribosome to the ER. There, the ribosome feeds its amino acid chain into the ER lumen (interior) as it's made.
In some cases, the signal peptide is snipped off during translation and the finished protein is released into the interior of the ER (as shown above). In other cases, the signal peptide or another stretch of hydrophobic amino acids gets embedded in the ER membrane. This creates a transmembrane (membrane-crossing) segment that anchors the protein to the membrane.
Transport through the endomembrane system
In the ER, proteins fold into their correct shapes, and may also get sugar groups attached to them. Most proteins are then transported to the Golgi apparatus in membrane vesicles. Some proteins, however, need to stay in the ER and do their jobs there. These proteins have amino acid tags that ensure they are shipped back to the ER if they "escape" into the Golgi.
"The endomembrane system and proteins: Figure 1," by OpenStax College, Biology (CC BY 3.0).
In the Golgi apparatus, proteins may undergo more modifications (such as addition of sugar groups) and before going on to their final destinations. These destinations include lysosomes, the plasma membrane, and the cell exterior. Some proteins need to do their jobs in the Golgi (are "Golgi-resident), and a variety of molecular signals, including amino acid tags and structural features, are used to keep them there or bring them back.
If they don't have any specific tags, proteins are sent from the Golgi to the cell surface, where they’re secreted to the cell exterior (if they’re free-floating) or delivered to the plasma membrane (if they’re membrane-embedded). This default pathway is shown in the diagram above for a membrane protein, colored in green, that bears sugar groups, colored in purple.
Proteins are shipped to other destinations if they contain the right molecular labels. For example, proteins destined for the lysosome have a molecular tag consisting of a sugar with a phosphate group attached. In the Golgi apparatus, proteins with this tag are sorted into vesicles bound for the lysosome.
Targeting to non-endomembrane organelles
Proteins that are made in the cytosol (don't enter ER during translation) may stay permanently in the cytosol. However, they may also be shipped to other, non-endomembrane destinations in the cell. For instance, proteins bound for the mitochondria, chloroplasts, peroxisomes, and nucleus are usually made in the cytosol and delivered after translation is complete.
To be delivered to one of these organelles after translation, a protein must contain a specific amino acid "address label." The label is recognized by other proteins in the cell, which help transport the protein to the right destination.
As an example, let's consider delivery to the peroxisome, an organelle involved in detoxification. Proteins needed in the peroxisome have a specific sequence of amino acids called a peroxisomal targeting signal. The classic signal consists of just three amino acids, serine-lysine-leucine, found at the very end (C-terminus) of a protein. This pattern of amino acids is recognized by a helper protein in the cytosol, which brings the protein to the peroxisome.
Mitochondrial, chloroplast, and nuclear targeting are generally similar to peroxisomal targeting. That is, a certain amino acid sequence sends the protein to its target organelle (or a compartment inside that organelle). However, the nature of the "address labels" is different in each case.
[Credit: Khan Academy]
