Protein sorting involves targeting proteins within or outside the cell to specific intracellular locations such as organelles. The majority of proteins found in organelles are synthesised by ribosomes in the cytosol. These proteins require specific targeting signals in their amino acid sequence to transport them to the correct subcellular location.
Proteins which are destined for the cytosol do not require a targeting signal since they are already present in the cytosol. Therefore the cytosol can be considered as a 'default' for when a targeting signal is missing from a protein.
For a protein to be targeted to the nucleus it requires a nuclear localisation signal (NLS). This signal:
The process of importing a protein into the nucleus requires a nuclear import receptor and the small GTPase, Ran. The import of a protein into the nucleus involves:
The diagram below illustrates this process.
Proteins which are destined for the mitochondria are synthesised in the cytosol as the mitochondrial precursor proteins and have a mitochondrial targeting signal that is:
The signal also has a strong tendency to form an amphipathic alpha helix.
Proteins are imported into the mitochondria, unfolded and post-translationally modified. They bind to receptors found in the outer mitochondrial membrane and are then threaded through the translocation channel into the mitochondria.
Endoplasmic reticulum (ER) targeting signals:
Membrane proteins targeted to the ER also have a stop-transfer sequence or a signal anchor sequence as well as a targeting signal. A stop-transfer sequence prevents the complete tranfer of a protein and so is anchored in the membrane. As with the targeting signal, the stop-transfer signal is cleaved by a signal peptidase. The signal anchor sequence also anchors the protein in the membrane but is not removed.
The import of the protein into the ER, unlike other organelles, is co-translational. That is, the ribosome which synthesises the protein is directly attached to the ER membrane (rough endoplasmic reticulum). This allows the protein to be translocated into the ER while it is still being synthesised. However proteins can also be imported post translationally which involves:
The ER, along with the Golgi apparatus, lysosome and plasma membrane, make up the secretory pathway. Again, signals are needed to transport the proteins from the ER to the correct location in the pathway, the table below shows this.
Although the import process is not yet fully understood, it is known that there are two signals which can target a protein to the peroxisome:
Two signal sequences are required in order to target a protein to the thylakoid :
Sequence of steps required to import a protein into the thylakoid:
Cystic fibrosis is an example of an 'ER storage disease,' caused by a protein not being transported to its correct place. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in its inability to pump chloride ions out of the cell, causing the symptoms of the disease. However in some cases the mutated CFTR is still functional but is retained in the ER instead of being transported to the plama membrane. It is the removal of the functional CFTR which causes cyctic fibrosis.
Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter. Molecular Biology of the Cell 5th Ed, pgs 701-783, Garland Science 2008.
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