How molecular labels are used to direct proteins to different parts of the cell (and to the cell exterior).

Introduction

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.
Proteins all begin their synthesis in the cytosol. Many stay there permanently, but some are transported to other cellular destinations.
Some are completely synthesized in the cytosol. These may be imported into the mitochondrion, peroxisome, chloroplast, and nucleus via post-translational transport.
Other proteins are co-translationally imported into the endoplasmic reticulum. From there, most travel to the Golgi apparatus by vesicle transport. From the Golgi apparatus, proteins may travel (also by vesicle transport) to the cell exterior (for secretion), the plasma membrane, the lysosome, or other parts of the endomembrane system.
Diagram based on similar diagram in Alberts et al. 1^1.
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 translated2^2.
  • 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.
  1. Signal recognition particle (SRP) binds to the signal peptide as it emerges from the ribosome.
  2. SRP brings the ribosome to the ER by binding to a receptor on the ER surface. The receptor is associated with other proteins that make a pore.
  3. The ribosome resumes translating, feeding the polypeptide through the pore and into the ER lumen (interior).
  4. An enzyme associated with the pore snips off the signal peptide.
  5. Translation continues, and the growing amino acid chain slides into the ER lumen.
  6. The completed polypeptide is released into the ER lumen, where it floats freely.
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.
Image showing transport of a membrane protein from the rough ER, through the Golgi, to the plasma membrane. The protein is initially modified by the addition of branching carbohydrate chains in the rough ER; these are then trimmed back and replaced with other branching chains in the Golgi apparatus. The protein with its final set of carbohydrate chains is then transported to the plasma membrane in a transport vesicle. The vesicle fuses with the plasma membrane, its lipids and protein cargo becoming part of the plasma membrane.
_Image modified from "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 back3^3.
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.
Yes, they do! However, only some of the proteins found in these organelles are made using the internal ribosomes. Most proteins are actually made on ribosomes in the cytosol and imported to the mitochondria or chloroplasts after translation.
Learn more about why mitochondria and chloroplasts contain ribosomes in the article on mitochondria, chloroplasts, and peroxisomes.
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 peroxisome4^4.
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.
This article is licensed under a CC BY-NC-SA 4.0 license

Works cited:

  1. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002). A simplified “roadmap” of protein traffic. In Molecular biology of the cell (4th ed.). New York, NY: Garland Science. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK26907/figure/A2143/?report=objectonly.
  2. Purves, W.K., Sadava, D., Orians, G.H., and Heller, H.C. (2003). Chemical signals in proteins direct them to their cellular destinations. In Life: the science of biology (7th ed., p. 247). Sunderland, MA: Sinauer Associates.
  3. Banfield, D. K. (2011). Mechanisms of protein retention in the Golgi. Cold Spring Harbor Perspectives in Biology, 3, a005264. http://dx.doi.org/10.1101/cshperspect.a005264.
  4. Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P., Baltimore, D., and Darnell, J. (2000) Synthesis and targeting of peroxisomal proteins. In Molecular cell biology (4th ed., section 17.2). New York, NY: W. H. Freeman. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK21520/.

References

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Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002). Transport from the ER through the Golgi apparatus. In Molecular biology of the cell (4th ed.). New York, NY: Garland Science. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK26941/.
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Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Gene expression: from gene to protein. In Campbell biology (10th ed., pp. 333-359). San Francisco, CA: Pearson.
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