What is the role of a mannose 6-phosphate residues in the sorting of protein?

Mannose-6-phosphate (M6P) residues play a critical role in the targeting and sorting of lysosomal enzymes from the trans-Golgi network to the lysosomes. This is one of the most well-known examples of protein sorting signals that help direct enzymes to their correct destination inside the cell.

Lysosomes are cellular organelles responsible for breaking down macromolecules with the help of hydrolytic enzymes. These enzymes are synthesized in the rough endoplasmic reticulum (RER) and pass through the Golgi apparatus before reaching the lysosomes. However, they do not go to the lysosomes randomly. They are specifically tagged with mannose-6-phosphate residues, which act like an "address label" for lysosomal targeting.

The process involves the following key steps:

1. Addition of Mannose-6-Phosphate in the Golgi:

After synthesis in the RER, lysosomal enzymes enter the cis-Golgi, where they undergo post-translational modification. In the cis and medial Golgi, a special enzyme called N-acetylglucosamine-1-phosphotransferase adds a phosphorylated GlcNAc group to a mannose residue on the enzyme's oligosaccharide chain. Later, another enzyme removes the GlcNAc group, leaving behind a mannose-6-phosphate (M6P) residue.

2. Recognition by Mannose-6-Phosphate Receptors (MPRs):

In the trans-Golgi network, these M6P-tagged enzymes are recognized by mannose-6-phosphate receptors (MPRs). These receptors bind specifically to the M6P tag and help package the enzyme into clathrin-coated vesicles, along with adaptor proteins like AP1.

3. Vesicle Transport to Endosomes and Lysosomes:

The clathrin-coated vesicles then bud off from the trans-Golgi and move toward early endosomes. As the vesicle matures into a late endosome, the pH becomes more acidic, causing the enzyme to dissociate from the MPR.

4. Recycling of Receptors:

After delivering the enzyme, the M6P receptors are recycled back to the Golgi for reuse, while the enzymes are delivered to the lysosome, where they become active and begin digesting cellular materials.





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