Mannose-6-phosphate targeting of enzymes to lysosomes
Mannose-6-phosphate, a mannose sugar carrying a phosphate group, is the tag the Golgi apparatus adds to many lysosomal enzymes (the digestive enzymes inside the lysosome) to send them there.
Remember
In the Golgi, many lysosomal enzymes are tagged with mannose-6-phosphate, and a receptor that recognises the tag directs them to the lysosome.
Memory aid
Think of the tag as a postcode
Like a postcode on a parcel, the tag decides where the enzyme goes, and a protein without one follows the default route.
A protein with no sorting signal leaves the Golgi apparatus by the default route: a vesicle (a small membrane-bound bubble) carries it to the cell surface, and it is secreted. Lysosomes are full of acid hydrolases (enzymes that cut chemical bonds by adding water), and these enzymes need an address label so that they are not secreted.
For most soluble acid hydrolases (those that do not span a membrane), that label is mannose-6-phosphate (M6P). Enzymes in the Golgi add it to mannose sugars within the N-linked oligosaccharides (the sugar chains attached to the protein). The tag is only added if the protein has the right signal patch, a set of amino acids from different parts of the chain that sit together once the protein has folded.
In the trans-Golgi (the side of the Golgi where vesicles leave), the mannose-6-phosphate receptor binds the tag. The enzyme is then packaged into a vesicle that carries it through the endosomes (the sorting compartments between the Golgi and the lysosome) towards the lysosome. Inside the acidic endosome the enzyme comes off the receptor. The receptor is recycled to the Golgi, and the enzyme continues to the lysosome.
Lysosomal membrane proteins are sorted by signals of their own rather than by the mannose-6-phosphate route. A minority of soluble lysosomal proteins use other receptors, such as LIMP-2 or sortilin.
Key facts
- Where the tag is added
- Enzymes in the Golgi apparatus add mannose-6-phosphate to mannose sugars within the N-linked oligosaccharides.
- Signal patch
- The tag is only added if the protein has a signal patch, amino acids from different parts of the chain that sit together once the protein has folded.
- Reading the tag
- The mannose-6-phosphate receptor in the trans-Golgi binds the tag, and the enzyme is packaged into a vesicle bound for the lysosome.
- Release
- In the acidic endosome the enzyme comes off the receptor, the receptor is recycled to the Golgi apparatus, and the enzyme continues to the lysosome.
- Phosphate removal
- The phosphate group is removed, which stops the lysosomal protein returning to the Golgi apparatus.
- Clinical link
- A fault in GlcNAc-1-phosphotransferase, the enzyme that carries out the first step of adding the tag, causes the lysosomal storage diseases mucolipidosis types II and III. If the tagging enzyme is missing, as in mucolipidosis II, lysosomal enzymes are secreted instead.
Exam traps
- Ubiquitin is a small protein tag best known for marking proteins for destruction by the proteasome, the cell's protein-shredding machine, so attaching it does not send an enzyme to the lysosome; the sugar-phosphate tag does that.
- A KDEL sequence (lysine-aspartate-glutamate-leucine) does not send enzymes to lysosomes, because it lets a KDEL receptor return escaped proteins from the Golgi to the endoplasmic reticulum, which keeps them in the endoplasmic reticulum.
- A signal peptide (a short sequence that sends a new protein into the endoplasmic reticulum) does not pick the lysosome, because it only starts the protein on the secretory route; where the protein goes next is decided later in the Golgi.
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