Leader sequences are not signal peptides.
Although the double use of leader sequences to also depict signal peptides is accepted by the International Union of Pure and Applied Chemistry1and the DNA Database of Japan (DDBJ)/European Molecular Biology Laboratory (EMBL, Heidelberg, Germany)/GenBank (http://www.ebi.ac.uk/embl/Documentation/ FT_definitions/feature_table.html), we think the openness of the concept depending on the context is misleading and neglects the significance of leader sequences.
In eukaryotes, the signal peptide of a nascent precursor protein (pre-protein) directs the ribosome to the rough endoplasmic reticulum (ER) membrane and initiates the transport of the growing peptide chain across it.
In prokaryotes, the signal peptide directs the pre-protein to the cytoplasmic membrane. However, the signal peptide is not responsible for the final destination of the mature protein; secretory proteins devoid of further address tags in their sequence are by default secreted to the external environment.
Fig 1. Typical structure of a signal peptide and of a leader sequence.
Although signal peptides are not highly conserved, they have a common positively charged n-region, a hydrophobic h-region and a neutral, polar c-region (Fig. 1a). The c-region contains a weakly conserved cleavage site recognized by membrane-bound signal peptidases. Before the translocation of the pre-protein across the ER membrane, a ribonucleoprotein called signal recognition particle (SRP) binds to the signal peptide emerging from the ribosome. Then the SRP–signal peptide–ribosome complex binds to the ER membrane via an SRP receptor. The signal peptide is then inserted into the ER membrane via a signal peptide binding protein and the nascent polypeptide then crosses the ER membrane through a transmembrane channel.
In prokaryotes, pre-proteins are translocated through the cytoplasmic membrane via a similar mechanism. During the translocation across the ER membrane in eukaryotes and the cytoplasmic membrane in prokaryotes, the signal peptide is normally cleaved off the preprotein by a signal peptidase residing in the ER or cytoplasmic membrane.
Leader sequences comprise a short open reading frame coding for a leader peptide and a downstream adjacent region with the propensity of forming mutually exclusive secondary structures (stem-loops) by basepairing of complementary sequences. The formation of one or the other possible stemloops depends on stalling of the ribosome during translation of the leader peptide, either because of lack of the necessary tRNA or because of binding of a specific metabolite to the ribosome/mRNA complex.
In turn, the formation of the alternative mRNA conformation affects either the continuation of transcription (transcriptional attenuation) or the initiation of translation of the protein coding region (translational attenuation).
Thus, leader sequences may regulate gene expression at the level of transcription or translation. The structure is summarized in Figure 1b. The type of transcriptional attenuation mechanisms seen in prokaryotic leader sequences also occur in operons encoding enzymes involved in the biosynthesis of other amino acids, antibiotic resistance and glucoside uptake and metabolism. Translational attenuation occurs in antibiotic resistance (e.g., the ermC gene of Staphylococcus aureus).
In eukaryotes, transcription and translation are physically separated and regulation of gene expression is more complex, involving, for example, mRNA processing. However, leader sequences are also involved in gene expression in eukaryotes and examples of leader sequence–dependent regulation of translation have been described.
Reference:
1. Mølhøj M, Degan FD. Leader sequences are not signal peptides. Nature Biotechnology. 2004;22(12):1502-1502. doi:10.1038/nbt1204-1502
Souce: NovoPro 2018-04-21