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.

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

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.

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).

Educational information, not medical advice. For any symptom, see a health professional.

Sources: PDB-101: Molecule of the Month: Importins (RCSB Protein Data Bank (PDB-101), 2026); PDB-101: Molecule of the Month: Nuclear Pore Complex (RCSB Protein Data Bank (PDB-101), 2026); PDB-101: Molecule of the Month: Oligosaccharyltransferase (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).

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Representative model, for educational purposes only.