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#M6P

2 public questions tagged with this topic.

Protein Sorting and Trafficking

What happens if a mutation prevents phosphorylation of Mannose-6-Phosphate (M6P)?

Targeting soluble acid hydrolases to lysosomes hinges on carbohydrate tag mannose-6-phosphate discovered by fractionation. In cis-Golgi, UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase alpha2 beta2 gamma2 recognizes structural patch including lysine residues clustered in tertiary structure on hydrolases like cathepsin B and adds GlcNAc-phosphate to terminal mannose of high-mannose N-glycans. Uncovering in TGN by NAGPA removes GlcNAc exposing M6P monoester capable of binding M6P receptors. M6P receptors divert enzymes from default secretory flow into clathrin-AP1 and GGA vesicles destined to late endosomes where acid releases enzyme. If phosphorylation fails due to loss-of-function mutation in GNPTAB encoding alpha beta subunits, as in mucolipidosis II I-cell disease and milder III pseudo-Hurler, hydrolases lack tag cannot bind receptors therefore traverse default secretory conduit to plasma membrane and secreted with high extracellular activity detectable in serum. Lysosomes deficient in over 50 hydrolases accumulating undigestible glycosaminoglycans and sphingolipids forming inclusion bodies pathognomonic. Glycosylation otherwise normal, ER-Golgi transport persists, but lysosomal delivery selectively lost causing severe multisystem disease.

Ref: Alberts et al., MBC: I-cell disease defective GlcNAc-phosphotransferase causes lysosomal enzyme secretion.

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Protein Sorting and Trafficking

What type of signal directs proteins from the Golgi to lysosomes?

Soluble acid hydrolases that degrade macromolecules inside lysosomes must be diverted from default secretory flow that would otherwise release them extracellularly. In cis-Golgi, UDP-GlcNAc: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, itself activated by Site-1 protease cleavage, adds GlcNAc-1-phosphate to carbon-6 hydroxyl of selected mannose residues on N-linked high-mannose oligosaccharides of hydrolase precursors arriving from ER. A second enzyme, uncovering enzyme, removes GlcNAc leaving mannose-6-phosphate monoester exposed. In trans-Golgi network, two mannose-6-phosphate receptors, cation-dependent MPR46 and cation-independent MPR300, recognize clustered phosphomannose with high avidity using mannose-6-phosphate homology domains, concentrating cargo into clathrin-coated vesicles assembled by GGA and AP-1 adaptors that bind dileucine and acidic motifs in receptor tails. Vesicles fuse with early and late endosomes where acidic pH near 5.5 triggers ligand dissociation, receptors recycle to Golgi for reuse, and hydrolases continue to lysosomes where phosphatase removes tag. Inherited deficiency in phosphotransferase causes I-cell disease with hypersecretion, proving essentiality of Golgi-based mannose-6-phosphate code for lysosomal biogenesis and intracellular digestion. Additional coordination with cellular stress pathways ensures fidelity, prevents aggregation, and links trafficking to growth control and proteostasis maintenance across diverse cell types and developmental stages.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 13: Mannose-6-Phosphate Tagging for Lysosomal Targeting.

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