How molecular labels are used to direct proteins to different parts of the cell (and to the cell exterior).
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.
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.
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.
- Signal recognition particle (SRP) binds to the signal peptide as it emerges from the ribosome.
- 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.
- The ribosome resumes translating, feeding the polypeptide through the pore and into the ER lumen (interior).
- An enzyme associated with the pore snips off the signal peptide.
- Translation continues, and the growing amino acid chain slides into the ER lumen.
- 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.
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.
Want to join the conversation?
- Can you explain all the initiation factors in both prokaryotes and eukaryotes. what their purpose is and how they function.(5 votes)
- Explaining all of the initiation factors is probably beyond the scope of this introductory article.
There are three initiation factors for translation in prokaryotes. For anyone who wants to know how they work, you can read a review paper here; http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2958.1998.00893.x/epdf
As for eukaryotic translation initiation factors, that's even more complex! I'm not sure we even know exactly how they all work yet. You can view a summary table of them here:
And there is a slightly longer explanation of how some of them work here:
- Can you please tell more about adding sugars to the proteins, their purpose and functions. It would be wonderful if you'll explain chemical mechanism as well. Thank you))(5 votes)
- The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation.
It helps in folding proteins.
Carbohydrate groups are added via glycosidic bonds.(3 votes)
- First of all, thank you for the helpful article!
I have some questions considering this article:
1. What do you mean by molecular tags? Do you mean other signal peptides like the NLS which is on amino acids that are destined for the nucleus?
2. And what other factors except signal peptides determine the final destination of the protein in the cell?
Thank you for your time
- 1. Molecular tags are used in genomic sequencing as a method but also as a natural process in the cell. So you are correct, plasmid NL5 can be considered as used for molecular tagging.
2. Glycosylation, molecular chaperones...(2 votes)
- Do proteins that are formed in the cytosol undergo further modification (e.g. folding)?(2 votes)
- Yes, proteins do undergo folding (some of them). Linear proteins not, but those with tertiary and especially quaternary structure (assembling of subunits) undergo further modifications and interactions depending on other signalling molecules in the cell.
That is considered as post-translational modification
- In the second stage of translation in gene expression--elongation, ribosomes are said to provide tRNA as well as amino acids to bind to codons in the mRNA strand in chemical reactions with aminoacyl-tRNA synthetase.My question is, do the ribosomes provide the tRNA and amino acid materials themselves? (Since they are made up of 2/3 tRNA strands and 1/3 protein) If so, how do they replenish their storage of tRNA and proteins? Are some of the proteins made after translation used to replenish their storage?(2 votes)
- Ribosomes are made of two subunits. Each of proteins and rRNA. Not tRNA.
Yes their role is to catch mRNA in sandwich structure and to attract tRNA, but they are composed of rRNA.
- If a polypeptide with a signal-anchor sequence is made, would and example of a function be a transmembrane protein?(2 votes)
- Do you mean a signal peptide mentioned in this article? Yes, those proteins will have transmembrane parts at least. They may just span the membrane once, or several times. Proteins with transmembrane portions can have many functions, such as receptors or ion channels.
There are also other ways to 'anchor' a protein to a membrane, but then the protein is not really in the membrane and not a transmembrane protein. In these cases the protein is attached to a lipid which associates with the membrane.(1 vote)
- Does the signal sequence is cleaved off after entering the different organells to which it's targetted for?(1 vote)
- Can someone please discuss the energy requirements for this process? Thanks.(1 vote)
- In which organelle does a protein, just synthesized from the ribosomes on the rough ER, fold into its tertiary/quaternary structure?(1 vote)
- It can travel to the Golgi apparatus or getting delivered vesicles from the Golgi apparatus.(1 vote)
- What happens to proteins that are just left in the Cytosol(1 vote)
- If they are structural then they will be embedded in the cytoskeleton and somehow do their job
If they are functional like the cytosolic glycolytic enzymes then they will do their job as required.
Both kinds of these cytosolic proteins will do their job and function properly till the cell no longer needs them or the protein dysfunctions for some reason. In such a scenario, the protein will be ubiquinated and hydrolyzed in the lysosome consequently.(1 vote)