[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Protein targeting and signal sequences [Biochemistry](https://durgical.com/en/biochemistry/) · Topic # Protein targeting and signal sequences Each new protein carries an 'address label' in its sequence that tells the cell where to send it: ER, nucleus, mitochondrion, peroxisome or lysosome. Updated 2026-11-01 ## Key facts - Secreted, membrane, ER, Golgi and lysosomal proteins have an N-terminal hydrophobic signal peptide; the signal recognition particle (SRP) pauses translation and brings the ribosome to the ER translocon (Sec61). - The signal peptide is cut off in the ER by signal peptidase; proteins without other signals are secreted by default. - Other labels: KDEL (C-terminal) keeps proteins in the ER; mannose 6-phosphate sends hydrolases to lysosomes; a nuclear localisation signal (NLS, Lys/Arg-rich) brings proteins through the nuclear pore with importins. - Mitochondrial proteins carry an N-terminal amphipathic presequence and are imported after translation through the TOM and TIM complexes; peroxisomal proteins carry PTS1 (C-terminal Ser-Lys-Leu, SKL) or PTS2. - Proteins with no signal stay in the cytosol. ## In detail - 1. Co-translational route: as the signal peptide emerges, SRP binds it and the ribosome; SRP docks on its receptor in the ER membrane (both use GTP) and the chain threads through Sec61. - 2. Membrane proteins have hydrophobic stop-transfer and signal-anchor segments that leave them embedded in the bilayer. - 3. In the ER the protein is folded with chaperones (BiP), forms disulfide bonds and is N-glycosylated; then it travels to the Golgi in COPII vesicles (COPI returns escapees). - 4. From the trans-Golgi network proteins are sorted to secretory granules (regulated secretion), the plasma membrane (constitutive secretion) or lysosomes. - 5. Post-translational routes (nucleus, mitochondria, peroxisomes) import fully made proteins; chaperones keep them unfolded for import into mitochondria. - 6. Nuclear import and export use the Ran-GTP gradient: high Ran-GTP in the nucleus releases cargo from importins. **Also called** Protein sorting, Signal peptide and SRP, Nuclear localisation signal ## Clinical notes - Zellweger syndrome: PEX gene defects block import of peroxisomal enzymes (PTS1/PTS2), and very-long-chain fatty acids accumulate. - In primary hyperoxaluria type 1, some AGXT variants send the peroxisomal enzyme to mitochondria by mistake, where it cannot work. - In I-cell disease, lysosomal hydrolases lack mannose 6-phosphate and are secreted instead of reaching lysosomes; Z α1-antitrypsin is retained in the ER of hepatocytes. ## Related conditions - [Zellweger syndrome (Zellweger spectrum)](https://durgical.com/en/conditions/zellweger-syndrome/) - [I-cell disease (mucolipidosis II)](https://durgical.com/en/conditions/i-cell-disease/) - [α1-antitrypsin deficiency](https://durgical.com/en/conditions/1-antitrypsin-deficiency/) - [Primary hyperoxaluria](https://durgical.com/en/conditions/primary-hyperoxaluria/) ## Related - [Glycoproteins and protein glycosylation (N- and O-linked)](https://durgical.com/en/biochemistry/topics/glycoproteins-and-protein-glycosylation/) - [Molecular chaperones and heat shock proteins](https://durgical.com/en/biochemistry/topics/molecular-chaperones-and-heat-shock-proteins/) - [Ubiquitin–proteasome system](https://durgical.com/en/biochemistry/topics/ubiquitin-proteasome-system/) - [Mannose 6-phosphate tagging (sending enzymes to the lysosome)](https://durgical.com/en/biochemistry/topics/mannose-6-phosphate-tagging/) - [Cell organelles and their metabolism](https://durgical.com/en/biochemistry/topics/cell-organelles-and-their-metabolism/) - [Peroxisomal oxidation (β- and α-oxidation)](https://durgical.com/en/biochemistry/topics/peroxisomal-oxidation/) - [Membrane transport](https://durgical.com/en/biochemistry/topics/membrane-transport/) - [Translation and the genetic code](https://durgical.com/en/biochemistry/topics/translation-and-the-genetic-code/) ## Test yourself Think of the answer, then tap the question to see it. ## What recognises the signal peptide of a secreted protein as it leaves the ribosome? The signal recognition particle (SRP), which pauses translation and docks the ribosome on the ER translocon. ## Which C-terminal sequence keeps soluble proteins in the ER? KDEL (Lys-Asp-Glu-Leu), recognised by a receptor that returns escaped proteins from the Golgi. ## What signal targets proteins to the peroxisomal matrix? PTS1, a C-terminal Ser-Lys-Leu (SKL), or the N-terminal PTS2. ## What happens to a protein made on free ribosomes with no targeting signal? It stays in the cytosol. ## What defect causes Zellweger syndrome? Failure to import peroxisomal matrix proteins because of mutations in PEX genes (peroxins). [Add to my cards (5)](https://durgical.app/estudiar/?add=/en/biochemistry/topics/protein-targeting-and-signal-sequences/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [PDB-101: Molecule of the Month: Importins](https://pdb101.rcsb.org/motm/85) (RCSB Protein Data Bank (PDB-101), 2026); [PDB-101: Molecule of the Month: Nuclear Pore Complex](https://pdb101.rcsb.org/motm/205) (RCSB Protein Data Bank (PDB-101), 2026); [PDB-101: Molecule of the Month: Oligosaccharyltransferase](https://pdb101.rcsb.org/motm/266) (RCSB Protein Data Bank (PDB-101), 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011). [← All of biochemistry](https://durgical.com/en/biochemistry/) ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/biochemistry/topics/protein-targeting-and-signal-sequences/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/topics/protein-targeting-and-signal-sequences/