Intracellular transport
Intracellular transport

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Intracellular transport

4.2 Peptide signal sequences

The distinct chemistry of proteins at the N- and C-termini provides protein molecules with two positionally and chemically unique sites for post-translational modifications and with the means to control their spatial and temporal interactions and position. This feature of proteins is crucial for a variety of biological processes from protein degradation to protein sorting for specific cellular compartments. The N- and C-termini of proteins have distinct roles, and we have already emphasised the importance of the N-terminal signal sequence in controlling translation across the ER.

Proteins destined for other cellular compartments also have signal sequences. For example, more than 98% of mitochondrial proteins are synthesised as pre-proteins in the cytosol, and these proteins contain a targeting sequence at the N-terminus, called a presequence, which is made up of 20–50 amino acid residues with characteristic properties. This sequence is enriched with positively charged hydroxylated and hydrophobic residues and has the potential to form an amphiphilic α helix. The sequence is recognised by protein translocator complexes located in both the inner and outer mitochondrial membranes.

Import of proteins to the nucleus and to the chloroplast also depends on the N-terminal signal peptides. It is possible to change the localisation of a protein by genetic engineering – attachment of appropriate presequences can direct non-mitochondrial proteins to mitochondria and across both outer and inner membrane into the matrix. This demonstrates that they contain all the information needed for targeting and membrane translocation properties. In plants, a group of proteins known as dual-targeted proteins have a targeting peptide capable of leading the mature protein to both organelles, that is to mitochondria and chloroplasts. Dual-targeted proteins not only have to be recognised by the import apparatus of two different organelles, but their targeting peptide must be correctly removed once the protein is inside the organelle.

Signals at the C-terminus are also important, but have different functions. We have already mentioned the tetrapeptide signals KDEL and KKXX of lumenal and transmembrane ER proteins, and their interaction with corresponding receptors that forms the basis for ER localisation and retrieval activity. Other examples are the diacidic DXE motif or the FCYENE motif both involved in ER export. The sorting function of a signalling peptide is not restricted to proteins that enter the secretory pathway. For example, two types of peroxisomal targeting signal mediate the import of most peroxisomal matrix proteins.

Abnormal proteins can arise as a result of various mechanisms, including premature termination of translation. To channel these proteins into a degradation pathway, an 11-residue C-terminal sequence with a non-polar tail,-AANSENYALAA-COOH, is added to the protein. This sequence serves as a signal for protease recognition in various cellular compartments. Although it is relatively easy to spot signal sequences in molecules, signal patches that rely on particular protein folding are less easy to identify. Table 5 shows some examples of signal sequences.

Table 5 Signal sequences

Function of signal sequenceExample of signal sequence
import into nucleusPPKKKRKV
export from nucleusLALKLAGLDI
import into mitochondria


import into peroxisomeSKL-COO
import into ER


return to ERKDEL-COO
Important hydrophobic amino acids are underlined; +H3N indicates the N-terminus of a protein; COO indicates the C-terminus; the positions of a key set of positively charged residues in the mitochondrial import sequence, which cluster on one side of the α helix, are shown in bold. (Information derived from Alberts, et al., 2002).

Because many viruses replicate in the nucleus of their host cells (e.g. influenza virus, HIV-1), they have developed several methods for transporting their genome into this compartment using the complex machinery that cells have evolved for protein and nucleic acid trafficking. After viral entry into the cell, either through endocytosis (influenza virus) or via fusion with the plasma membrane (HIV-1), the nucleic acids (associated with virus-specific proteins) are discharged into the cytoplasm. This nucleoprotein capsid must make its way to the nucleus. To gain access to the nucleus, viruses use two different methods: (i) they wait in the cytosol until the cell undergoes mitosis, or (ii) they use strategies that enlist the cellular nuclear transport machinery, but which also depend on the size of the viral capsid. The only way for macromolecules to enter the nucleus is through the nuclear pore complex (NPC), and the mechanism depends on the ‘nuclear localisation sequences’ (NLS) exposed on the surface of the capsid particle.


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