Trends in Cell Biology
Volume 8, Issue 10, 1 October 1998, Pages 410-415
Journal home page for Trends in Cell Biology

Signal sequences: more than just greasy peptides

https://doi.org/10.1016/S0962-8924(98)01360-9Get rights and content

Abstract

Export signal sequences target newly synthesized proteins to the endoplasmic reticulum of eukaryotic cells and the plasma membrane of bacteria. All signal sequences contain a hydrophobic core region, but, despite this, they show great variation in both overall length and amino acid sequence. Recently, it has become clear that this variation allows signal sequences to specify different modes of targeting and membrane insertion and even to perform functions after being cleaved from the parent protein. This review argues that signal sequences are not simply greasy peptides but sophisticated, multipurpose peptides containing a wealth of functional information.

Section snippets

Signal sequences specify different pathways to a membrane

Signal sequences can direct proteins to a membrane through different targeting pathways and select different translocation systems for the actual transport across the membrane. Targeting and translocation can occur co- or post-translationally and can either be dependent on the signal recognition particle (SRP) and docking protein/SRP receptor or be SRP independent; in the latter case, targeting and translocation involve the SecB protein in bacteria and the Sec62p–Sec63p complex in yeast[2](Fig.

Signal sequences as membrane anchors

Signal sequences can anchor proteins in the membrane when they contain a sufficiently hydrophobic h-region and are not cleaved by signal peptidase. They are then called `signal-anchor' sequences to indicate their dual function in targeting and membrane anchoring[31]. Signal-anchor sequences can insert into the membrane in either orientation, keeping the N-terminus on the cytoplasmic side or transferring it across the membrane. During biosynthesis of a type II membrane protein, the nascent

A signal sequence can target to more than one location

Signal sequences can differ in the efficiency by which they mediate targeting and membrane insertion. The cytosolic and secreted forms of the plasminogen activator inhibitor (PAI), for instance, are generated by variable translocation—that is, only some of the proteins are translocated, whereas others remain cytosolic[18]. Similarly, a signal-anchor sequence can mediate the adoption of different topologies in the membrane. During biogenesis, the hepatitis B virus large envelope protein inserts

Signal sequence cleavage

When N-terminal signal sequences insert into the membrane in a loop-like configuration, they can be cleaved by signal peptidase on the lumenal or trans side of the membrane. Whether cleavage does or does not occur depends on many features of the signal sequence, in particular on the amino acids at positions −3 and −1 N-terminal of the cleavage site. Cleavage can occur when an amino acid with a short side chain is present at the −1 position and charged amino acids are absent from the −3 position

Signal peptide fragments in the cytosol

Signal sequences that have been cleaved from precursor proteins are further processed by signal peptide peptidases. In Escherichia coli, cleaved signal sequences are processed by the membrane-bound protease IV and further degraded by cytosolic oligopeptidase A[47], but there are no known eukaryotic homologues of these proteins. Signal sequence processing clearly also happens in eukaryotic cells because signal peptide fragments occur in the cytosol[19]and bind to major histocompatibility complex

Presentation of signal peptide fragments by classical MHC class I molecules

Classical (polymorphic) MHC class I molecules HLA-A, -B and -C in human bind to peptides derived from pathogens or cellular proteins and present them on the cell surface to cytotoxic T cells[55]. Analysis of peptides presented by classical MHC class I molecules has shown that they are derived mostly from cytosolic proteins, degraded by the proteasome and transported by the transporter of antigen presentation (TAP) into the ER lumen. In the ER lumen, these peptides bind to MHC class I molecules,

Presentation of signal peptide fragments by nonclassical MHC class I molecules

Peptides presented by classical MHC class I molecules represent the broad spectrum of peptides generated by the proteasome. In contrast to this general use of peptides, only a very specific signal peptide fragment is presented by so-called nonclassical MHC class I molecules (HLA-E in human)20, 59. These molecules monitor the presence of classical MHC class I molecules by presenting a signal peptide fragment derived from HLA-A, -B or -C to natural killer (NK) cells (Fig. 5b). NK cells destroy

Conclusions and perspectives

The high degree of sequence and length variation of signal sequences, which has long been a puzzle, is now revealed as the basis for an amazing complexity and versatility of signal sequence function. Signal sequences have emerged as information-rich peptides. Furthermore, they have shown us that even small peptides can engage in many functions during their life span. We are still at the beginning of the path to elucidation of the full functional potential of signal sequences. They may specify

Acknowledgements

We thank M. Pool and G. Warren for critically reading the manuscript and the reviewers for useful suggestions. The work was supported by the Deutsche Forschungsgemeinschaft and the ETH Zürich.

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