Mannose 6-phosphate receptor
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
[1] Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments.
[6] Elizabeth Neufeld was studying patients who had multiple inclusion bodies present in their cells.
It is thought that they have evolved from the same ancestral gene as there is conservation in some of their intron/ exon borders and there is a homology in their binding domains.
Lysosomal enzymes are synthesised in the rough endoplasmic reticulum along with a range of other secretory proteins.
Once the lysosomal enzyme has been translocated into the rough endoplasmic reticulum an oligosaccharide composed of Glc3Man9GlcNAc2 is transferred en bloc to the protein.
[1] The oligosaccharide present on lysosomal enzymes is processed in the same manner as other secretory proteins whilst it is translocated from the endoplasmic reticulum to the cis-Golgi.
In the trans-Golgi a phosphodiesterase (EC 3.1.4.45) will remove the GlcNAc residue exposing the mannose 6-phosphate tag, allowing the lysosomal enzymes to bind to the CI-MPR and the CD-MPR.
The MPR-lysosomal enzyme complex is translocated to a pre-lysosomal compartment, known as an endosome, in a COPII-coated vesicle.
[11][12] This targeting away from the secretory pathway is achieved by the presence of a specific sorting signal, an acidic cluster/dileucine motif, in the cytoplasmic tails of the MPRs.
[14] Its function here is to capture any mannose 6-phosphate tagged enzymes that have accidentally entered the secretory pathway.
Approximately 70% of lysosomal enzymes are secreted in the absence of the CI-MPR – this suggests that the CD-MPR is unable to compensate for its loss.
When the CD-MPR is knocked out in mice they appear healthy apart from the fact that they have defects in the targeting of multiple lysosomal enzymes.
[7] From these knockout mice it can be deduced that both receptors are needed for the efficient targeting of lysosomal enzymes.
Combining these 3 domains allows the CI-MPR to bind to a wide range of phosphorylated glycan structures.
It is thought that when the CI-MPR is present on the cell surface, domain 11 will bind to any IGF-II free in the extracellular matrix.
The receptor is then rapidly internalised, along with IGF-II, through a YSKV motif present in the CI-MPR's cytoplasmic tail.
Due to CI-MPR's ability to modulate the levels of IGF-II it has been suggested it may play a role as a tumour suppressor.
[13] Studies of multiple human cancers have shown that a loss of the CI-MPR function is associated with a progression in tumourigenesis.
[18] Loss of heterozygosity (LOH) at the CI-MPR locus has been displayed in multiple cancer types including liver and breast.
