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Mannose 6-phosphate receptor
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa. The larger receptor is known as the cation-independent mannose 6-phosphate receptor (CI-MPR), while the smaller receptor (CD-MPR) requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
Both of these receptors bind terminal mannose 6-phosphate with similar affinity (CI-MPR = 7 μM, CD-MPR = 8 μM) and have similar signals in their cytoplasmic domains for intracellular trafficking.
Elizabeth Neufeld was studying patients who had multiple inclusion bodies present in their cells. Due to the large amount of inclusion bodies she named this condition I-cell disease. These inclusion bodies represented lysosomes that were filled with undigestable material. At first Neufeld thought these patients must have a lack of lysosomal enzymes. . Further study showed that all of the lysosomal enzymes were being made but they were being incorrectly targeted. Instead of being sent to the lysosome, they were being secreted. Furthermore, these mis-targeted enzymes were found to not be phosphorylated. Therefore, Neufeld suggested that I-cell disease was caused by a deficiency in the enzymes that add a specific mannose 6-phosphate tag onto lysosomal enzymes so they can be targeted to the lysosome.
Studies of I-cell disease led to the discovery of the receptors that bind to this specific tag. Firstly the CI-MPR was discovered and isolated through the use of affinity chromatography. However scientists discovered that some of the lysosomal enzymes still reached the lysosome in the absence of the CI-MPR. This led to the identification of another mannose 6-phosphate binding receptor, the CD-MPR, which binds its ligand in the presence of a divalent cation such as Mn2+.
The genes for each receptor have been cloned and characterised. 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.
The main function of the MPRs is to target lysosomal enzymes to the lysosome.
Lysosomal enzymes are synthesised in the rough endoplasmic reticulum along with a range of other secretory proteins. A specific recognition tag has evolved to prevent these harmful lysosomal enzymes from being secreted and to ensure they are targeted to the lysosome. This tag is a mannose 6-phosphate residue.
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Mannose 6-phosphate receptor
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa. The larger receptor is known as the cation-independent mannose 6-phosphate receptor (CI-MPR), while the smaller receptor (CD-MPR) requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
Both of these receptors bind terminal mannose 6-phosphate with similar affinity (CI-MPR = 7 μM, CD-MPR = 8 μM) and have similar signals in their cytoplasmic domains for intracellular trafficking.
Elizabeth Neufeld was studying patients who had multiple inclusion bodies present in their cells. Due to the large amount of inclusion bodies she named this condition I-cell disease. These inclusion bodies represented lysosomes that were filled with undigestable material. At first Neufeld thought these patients must have a lack of lysosomal enzymes. . Further study showed that all of the lysosomal enzymes were being made but they were being incorrectly targeted. Instead of being sent to the lysosome, they were being secreted. Furthermore, these mis-targeted enzymes were found to not be phosphorylated. Therefore, Neufeld suggested that I-cell disease was caused by a deficiency in the enzymes that add a specific mannose 6-phosphate tag onto lysosomal enzymes so they can be targeted to the lysosome.
Studies of I-cell disease led to the discovery of the receptors that bind to this specific tag. Firstly the CI-MPR was discovered and isolated through the use of affinity chromatography. However scientists discovered that some of the lysosomal enzymes still reached the lysosome in the absence of the CI-MPR. This led to the identification of another mannose 6-phosphate binding receptor, the CD-MPR, which binds its ligand in the presence of a divalent cation such as Mn2+.
The genes for each receptor have been cloned and characterised. 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.
The main function of the MPRs is to target lysosomal enzymes to the lysosome.
Lysosomal enzymes are synthesised in the rough endoplasmic reticulum along with a range of other secretory proteins. A specific recognition tag has evolved to prevent these harmful lysosomal enzymes from being secreted and to ensure they are targeted to the lysosome. This tag is a mannose 6-phosphate residue.