Signal sequence

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The signal sequence , also signal peptide or transit peptide, is a sequence of amino acids of a protein . This amino acid sequence determines the destination, the transport route of the protein within the cell and the secretion efficiency.

Occurrence and meaning

Signal sequences are typically found in proteins whose destination is outside the cell, in biomembranes or in compartments . A signal sequence is usually required for transport to the endoplasmic reticulum , chloroplasts , mitochondria , peroxisomes or the cell nucleus and their membranes. By combining different signal sequences, it is possible for proteins to be imported into different organelles at the same time, such as mitochondrion and chloroplast.

Although bacterial cells are not compartmentalized, bacterial proteins can have signal sequences. These can determine the proteins for transport into the cell membrane or the extracellular space.

Target compartments

Endoplasmic reticulum

Schematic representation of the signal sequence.

Transport into the lumen or membrane of the endoplasmic reticulum (ER) can take place during protein synthesis ( cotranslational protein transport ) or only as a finished protein that has previously been produced in the cytoplasm ( post-translational protein transport ). Proteins with more hydrophilic signal sequences are preferentially transported post-translationally.

Proteins with more hydrophobic signal sequences, on the other hand, are transported cotranslationally. This happens on the "rough ER", which is covered with ribosomes . The transport mechanism is complex and, in addition to the ribosome and the mRNA bound to it, also includes interacting proteins such as the signal recognition particle (SRP) and ribosome-associated proteins. In addition, an SRP receptor and the tunnel protein complex (SEC complex, translocon) are required in the membrane of the ER.

All secretory proteins and most proteins integrated into the membrane have a signal sequence of 15 to 50 amino acids in length at their N-terminus with certain properties. Signal sequences can also be found within a protein or at the C terminus.

The exact sequence of the individual amino acids is less important than their physical properties: a central hydrophobic core (h) is flanked at the N-terminal (n) by positively charged amino acids and at the C-terminal (c) by polar amino acids. The C-terminal area often contains helix-breaking amino acids such as proline or glycine . The N-terminal region is the least conserved. In most cases, the signal sequence is split off from the actual protein by the signal peptidase (SPase) after it has passed through the membrane. The interface is defined by small, uncharged amino acid residues in positions −3 and −1 of the C-terminal polar region of the signal sequence.

The amino acid sequence KDEL ensures that the protein is transported into the endoplasmic reticulum and retained therein; in the case of secretory proteins with a KDEL sequence, the signal sequence is cleaved off in the ER by proteolysis , as otherwise they are retained by the proteins KDELR1, 2 and 3, among other things.

particularities

In some transmembrane proteins , the first transmembrane domain is also the signal sequence. The segment, also known as the signal anchor sequence, is characterized by a longer hydrophobic core area and a lack of signal peptidase cleavage compared to the normal signal sequence.

The majority of the proteins that are transported to the ER have N-terminally oriented signal or signal anchor sequences. However, there are also integral membrane proteins that are inserted into the ER membrane without an N-terminal signal sequence. These proteins are recognized by a C-terminal hydrophobic segment. How these proteins insert into the ER membrane has not yet been clarified.

Cell nucleus

A signal sequence, here called nuclear localization signal (prototypical sequence PKKKRKV), is also required for post-translational protein import into the cell nucleus . This is recognized by a nuclear import receptor and transported into the nucleus together with it. Proteins are exported from the cell nucleus using an NES ( nuclear export signal ) via exportins and Ran-GTP with a G-protein- typical mechanism. The NES consists of the sequence LxxxLxxLxL with L representing aliphatic amino acids such as leucine and x for any amino acid.

Mitochondrion

The protein import into the mitochondrion takes place post-translationally, i.e. after protein biosynthesis has been completed. All import processes take place via the same transport machinery, the TOM complex ( translocase of the outer membrane ) of the outer mitochondrial membrane. There are also a number of other protein complexes that mediate the integration of proteins into the outer mitochondrial membrane (SAM complex, sorting and assembly machinery ), their import into the inner mitochondrial membrane and the mitochondrial matrix (TIM complex, translocase of the inner membrane ) .

Protein precursors can be divided into two groups: the first group consists of proteins with N-terminal signals that are intended for the mitochondrial matrix, some proteins of the inner membrane and the intermembrane space between the outer and inner membrane. The amino acid residues carry positive charges and interact with the import receptors of the organelle and also conduct it to their destination via the inner membrane. They generally consist of 20–40 amino acids that form an amphiphilic α-helix that is recognized by the importer. After the import, the signal sequence is cut off by a peptidase .

The second group includes all proteins of the outer membrane, many proteins of the inner membrane and the intermembrane space. They only carry internal signals that cannot be cut off.

Chloroplast

The protein import into the chloroplasts takes place post-translationally via the protein complexes TOC ( Translocase of the outer chloroplast membrane ) and TIC ( Translocase of the inner chloroplast membrane ).

Plastid signal peptides are located at the N-terminus of the protein precursor and have certain physical properties: they are rich in amino acids with hydroxylated residues, have no acidic residues and do not form secondary structure. The presequence is phosphorylated and interacts with the proteins Hsp70 and 14-3-3 , which accompany the protein to the transport apparatus. After the import, the signal sequence is cut off by a peptidase . The proteins of the outer membrane do not require an N-terminal signal peptide, the mechanism of integration is still unknown.

Proteins, whose destination is the membrane or the lumen of the thylakoids , can also contain additional signal sequences.

Peroxisome

The post-translational protein import into the peroxisome is based on two different types of signal sequences, which are called PTS1 and PTS2 (from English : Peroxisome Targeting Signal , for example "signals pointing to peroxisomes").

PTS1 sequences are short, C-terminal signals that contain the amino acid sequence from ( S / A / C ) - ( K / R / H ) - (L / L / M ). They are recognized by the peroxin-5 (Pex5p) receptor .

PTS2 sequences are 9 amino acid signals that are approximately 20 residues from the N-terminus. The receptor for PTS2 signals is Peroxin-7 (Pex7p).

literature

  • Lincoln Taiz, Eduardo Zeiger: Physiology of Plants. Spectrum Academic Publishing House, Heidelberg 2000, ISBN 3-8274-0537-8 .
  • Figueroa-Martinez, et al. : Reconstructing the Mitochondrial Protein Import Machinery of Chlamydomonas reinhardtii. In: Genetics. vol. 179 (1), 2008, pp. 149-155.
  • Joachim Rassow et al. : Dual series of biochemistry. Thieme Verlag, Stuttgart 2006, ISBN 3-13-125351-7 .

Individual evidence

  1. ↑ L. Kober, C. Zehe, J. Bode: Optimized signal peptides for the development of high expressing CHO cell lines . In: Biotechnol. Bioeng. tape 110 , no. 4 , April 2013, p. 1164–1173 , doi : 10.1002 / bit.24776 , PMID 23124363 .
  2. ↑ G. von Heijne: Signal sequences: The limits of variation . In: J Mol Biol . tape 184 , no. 1 , July 1985, p. 99-105 , doi : 10.1016 / 0022-2836 (85) 90046-4 , PMID 4032478 .
  3. ↑ Alexander Levitan et al .: Dual targeting of the protein disulfide isomerase RB60 to the chloroplast and the endoplasmic reticulum. In: Proc Natl Acad Sci USA . 102 (17), 2005, pp. 6225-6230 doi: 10.1073 / pnas.0500676102
  4. ↑ Susana Cristóbal et al: Competition between Sec-and TAT-dependent protein translocation in Escherichia coli. In: EMBO J . 18 (11), 1999, pp. 2982-2990. doi: 10.1093 / emboj / 11/18/2982
  5. ↑ G. Blobel , B. Dobberstein: Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. In: Journal of Cell Biology . 67 (3), 1975, pp. 835-851. PDF (free full text access)
  6. ↑ B. Martoglio, B. Dobberstein: Signal sequences: more than just greasy peptides. In: Trends Cell Biol . 8 (10), 1998, pp. 410-415. PMID 9789330 ; doi: 10.1016 / S0962-8924 (98) 01360-9
  7. ^ X. Xu, I. Meier: The nuclear pore comes to the fore. In: Trends Plant Sci. 13 (1), 2008, pp. 20-27 doi: 10.1016 / j.tplants.2007.12.001
  8. ^ Allison Lange et al .: Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin. In: J Biol Chem . 282 (8), 2006, S, pp. 5101-5105 doi: 10.1074 / jbc.R600026200
  9. ^ N. Wiedemann et al .: The protein import machinery of mitochondria. In: J Biol Chem . 279 (15), 2004, pp. 14473-14476. PMID 14973134
  10. ↑ a b M. Gutensohn et al: Toc, Tic, Tat et al.: Structure and function of protein transport machineries in chloroplasts. In: J Plant Physiol. 163 (3), 2006, pp. 333-347 doi: 10.1016 / j.jplph.2005.11.009
  11. ↑ Jürgen Soll, Enrico Schleiff: Plant cell biology: Protein import into chloroplasts. In: Nat Rev Mol Cell Biol . vol. 5, (3), 2004, pp. 198-208.
  12. ↑ a b L. A. Brown, A. Baker: Peroxisome biogenesis and the role of protein import. In: J Cell Mol Med. 7 (4), 2003, pp. 388-400. PMID 14754507

Web links

  • SPdb: Signal Peptide Resource (eng.) - Signal peptide database of the National University of Singapore & Macquarie University in Australia with currently 27,433 entries of archaea, prokaryote and eukaryote signal sequences (accessed October 20, 2009)