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Leader Sequences Are Not Signal Peptides

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Leader Sequences Are Not Signal Peptides CORRESPONDENCE Leader sequences are not signal peptides To the editor: An article in the June issue (Nat. Biotechnol. for the final destination 22, 773–774, 2004) highlights the challenge of the mature protein; A of producing a shared vocabulary that secretory proteins devoid biologists can use to communicate their results of further address tags effectively, explore data and extend scientific in their sequence are by B investigations. The success of ‘bio-ontologies’ default secreted to the will be dependent on the use of clearly defined external environment. scientific terms. In this context, we feel that Although signal ambiguities in the usage of the terms ‘leader peptides are not highly sequences’ and ‘signal peptides’ require conserved, they have clarification. a common positively Figure 1 Typical structure of a signal peptide and of a leader sequence. The translocation of secretory proteins across charged n-region, a (a) Structure of a signal peptide. Signal peptides do not consist of a intracellular membranes and final localization hydrophobic h-region strict consensus sequence but have a three-region design consisting of are mediated by ‘address tags’ contained within and a neutral, polar a positively charged N-terminal region (n-region), a hydrophobic central their amino acid sequences. Signal peptides, c-region (Fig. 1a). region (h-region) and a neutral, polar C-terminal region (c-region)3. (b) comprising the N-terminal 13–36 amino The c-region contains Layout of the trp operon and the location of the trp leader sequence. The trp operon codes for five enzymes (TrpA–TrpE) necessary for the acids of secretory proteins, are necessary for a weakly conserved biosynthesis of tryptophan. The trp leader sequence contains an open the translocation across the first membrane cleavage site recognized reading frame encoding the leader peptide and four CG-rich regions (1– on the secretory pathway and thus universally by membrane-bound 4) involved in regulating transcription and translation. Regions 1 and 2 http://www.nature.com/naturebiotechnology control the entry of all proteins to the secretory signal peptidases. Before form a transcriptional pause signal, and regions 3 and 4 a transcriptional pathway in eukaryotes and prokaryotes. Leader the translocation of termination signal (attenuator site). The figure is not drawn to scale. sequences are polynucleotide regions located the pre-protein across between the promoter and the coding region the ER membrane, a and are involved in the regulation of gene ribonucleoprotein called signal recognition Thus, leader sequences may regulate gene expression. Part of the leader sequence may particle (SRP) binds to the signal peptide expression at the level of transcription or be translated into a short leader peptide but, emerging from the ribosome. Then the translation. The structure is summarized in in contrast to signal peptides, leader peptides SRP–signal peptide–ribosome complex binds Figure 1b. are at no time part of the structural proteins. to the ER membrane via an SRP receptor. The The type of transcriptional attenuation mech- However, although signal peptides and leader signal peptide is then inserted into the ER anisms seen in prokaryotic leader sequences sequences clearly represent different entities membrane via a signal peptide binding protein also occur in operons encoding enzymes and have different functions they are often used and the nascent polypeptide then crosses the ER involved in the biosynthesis of other amino synonymously to depict signal peptides. membrane through a transmembrane channel. acids, antibiotic resistance and glucoside uptake © 2004 Nature Publishing Group Although the double use of leader sequences In prokaryotes, pre-proteins are translocated and metabolism. Translational attenuation to also depict signal peptides is accepted by through the cytoplasmic membrane via a occurs in antibiotic resistance (e.g., the ermC the International Union of Pure and Applied similar mechanism. During the translocation gene of Staphylococcus aureus5). In eukaryotes, Chemistry1and the DNA Database of Japan across the ER membrane in eukaryotes and transcription and translation are physically (DDBJ)/European Molecular Biology Labora- the cytoplasmic membrane in prokaryotes, the separated and regulation of gene expression is tory (EMBL, Heidelberg, Germany)/GenBank signal peptide is normally cleaved off the pre- more complex, involving, for example, mRNA (http://www.ebi.ac.uk/embl/Documentation/ protein by a signal peptidase residing in the ER processing. However, leader sequences are FT_definitions/feature_table.html), we think or cytoplasmic membrane. also involved in gene expression in eukaryotes the openness of the concept depending on Leader sequences comprise a short open and examples of leader sequence–dependent the context is misleading and neglects the reading frame coding for a leader peptide regulation of translation have been described6. significance of leader sequences. A clear and a downstream adjacent region with the definition of the leader sequence, such as the propensity of forming mutually exclusive Michael Mølhøj1 & Florence Dal Degan2 one provided by the Medical Dictionary Search secondary structures (stem-loops) by base- 1Micromet AG, Staffelseestrasse 2, D-81477 Engine (http://www.books.md/index.html) is pairing of complementary sequences. The Munich, Germany and 2Pharmexa A/S, Kogle Allé strongly preferred. To clarify the difference, we formation of one or the other possible stem- 6, DK-2970 Hørsholm, Denmark. briefly summarize below the general principles loops depends on stalling of the ribosome e-mail: [email protected] of signal peptides and leader sequences. during translation of the leader peptide, In eukaryotes, the signal peptide of a nascent either because of lack of the necessary tRNA 1. International Union of Pure and Applied Chemists. Compendium of Chemical Terminology, 2nd edition. precursor protein (pre-protein) directs the or because of binding of a specific metabolite (IUPAC, Research Triangle Park, NC, 1997). ribosome to the rough endoplasmic reticulum to the ribosome/mRNA complex. In turn, 2. Devillers-Thiery, A., Kindt, T., Scheele, G. & Blobel, G. Proc. Natl. Acad. Sci. USA 72, 5016–5020 (1975). (ER) membrane and initiates the transport the formation of the alternative mRNA 3. von Heijne, G. J. Membrane Biol. 115, 195–201 2,3 of the growing peptide chain across it . In conformation affects either the continuation (1990). 4 prokaryotes, the signal peptide directs the of transcription (transcriptional attenuation) 4. Platt, T. Cell 24, 10–23 (1981). 5. Weisblum, B. Antimicrob. Agents Chemother. 39, pre-protein to the cytoplasmic membrane. or the initiation of translation of the protein 797–805 (1995). However, the signal peptide is not responsible coding region (translational attenuation)5. 6. Rook, F. et al. Plant J. 15, 253–263 (1998). 1502 VOLUME 22 NUMBER 12 DECEMBER 2004 NATURE BIOTECHNOLOGY.
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