Summary: Cation-independent mannose-6-phosphate receptor repeat
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Mannose 6-phosphate receptor Edit Wikipedia article
|Cation-independent mannose-6-phosphate receptor repeat|
|Cation-dependent mannose-6-phosphate receptor|
|Locus||Chr. 12 p13|
|Cation-independent mannose-6 phosphate receptor|
|Locus||Chr. 6 q25q27|
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.
Mechanism of targeting
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.
Once the lysosomal enzyme has been translocated into the rough endoplasmic reticulum an oligosaccharide composed of Glc3 Man9 GlcNAc2 is transferred en bloc to the protein. 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 cis-Golgi a GlcNAc phosphotransferase (EC 18.104.22.168) adds a GlcNAc-1-phosphate residue onto the 6-hydroxyl group of a specific mannose residue within the oligosaccharide. This forms a phosphodiester: Man-phosphate-GlcNAc. Once the phosphodiester has been formed the lysosomal enzyme will be translocated through the Golgi apparatus to the trans-Golgi. In the trans-Golgi a phosphodiesterase (EC 22.214.171.124) 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 clathrin-coated vesicle. 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. Both MPRs bind their ligands most effectively at pH 6 – 7; thus enabling the receptors to bind to the lysosomal enzymes in the trans-Golgi and release them in the acidified environment of the endosome. Once the enzyme has dissociated from the mannose 6-phosphate receptor, it is translocated from the endosome to the lysosome where the phosphate tag is removed from the enzyme.
MPRs are not found in the lysosomes; they cycle mainly between the trans-Golgi network and endosomes. The CI-MPR is also present on the cell surface. Around 10-20% of the CI-MPR can be found at the cell membrane. Its function here is to capture any mannose 6-phosphate tagged enzymes that have accidentally entered the secretory pathway. Once it binds to a lysosomal enzyme the receptor becomes internalised rapidly. Internalisation is mediated by a sorting signal in its cytoplasmic tail – a YSKV motif. This ensures that all harmful lysosomal enzymes will be targeted to the lysosome.
Knockout mice studies
Mice lacking the CI-MPR die at day 15 of gestation due to cardiac hyperplasia. The mice suffer from abnormal growth because they are unable to regulate the levels of free IGF-II (insulin-like growth factor type II). Death of the mice can be prevented if the IGF-II allele is also knocked out. Further analysis of the embryos also showed that they display defects in the targeting of lysosomal enzymes as they have an increased level of phosphorylated lysosomal enzymes in their amniotic fluid. 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 we observe mice that appear healthy apart from the fact that they have defects in the targeting of multiple lysosomal enzymes. These mice display elevated levels of phosphorylated lysosomal enzymes in their blood and they accumulate undigested material in their lysosomes.
From these knockout mice we can deduce that both receptors are needed for the efficient targeting of lysosomal enzymes. If we compare the lysosomal enzymes that are secreted by the two different knockout cell lines we see different sets of enzymes. This suggests that each MPR interacts preferentially with a subset of lysosomal enzymes.
The CI-MPR and CD-MPR are structurally distinct receptors however they share an overall general structure as they are both type I integral membrane proteins. Both receptors have a large N-terminal extracytoplasmic domain, one transmembrane domain and a short C-terminal cytoplasmic tail. These cytoplasmic tails contain multiple sorting signals; some of which can be either phosphorylated or palmitoylated.
CI-MPR: The CI-MPR is ~300 kDa. The N-terminal extracytoplasmic domain contains 15 contiguous P-type carbohydrate recognition domains. They are referred to as MRH (mannose 6-phosphate receptor homology) domains. The domains are homologous because they have:
- A similar size - each one has around 150 amino acid residues
- Conserved amino acid residues – between 14-38% sequence identity 
- Conserved positioning of 6 specific Cysteine residues that are involved in forming disulphide bonds 
The structure of 7 out of the 15 domains has been determined, using X-ray crystallography, and they seem to share a similar fold. The CI-MPR exists mainly as a dimer in the membrane. Domains 3, 5 and 9 have been found to bind to mannose 6-phosphate. Domains 3 and 9 can bind to mannose 6-phosphate with high affinity. Domain 5 only binds Man-6-phosphate with a weak affinity. However domain 5 has also been shown to bind to the phosphodiester, Man-phosphate-GlcNAc. This is a safety mechanism for the cell – it means it is able to bind to lysosomal enzymes that have escaped the action of the enzyme that removes the GlcNAc residue. Combining these 3 domains allows the CI-MPR to bind to a wide range of phosphorylated glycan structures. Domain 11 binds to IGF-II.
CD-MPR: The CD-MPR is much smaller than the CI-MPR – it is only ~46 kDa. Its N-terminal extracytoplasmic domain contains only 1 P-type carbohydrate recognition domain. The CD-MPR exists mainly as a dimer in the membrane. However monomeric and tetrameric forms are also thought to exist as well. The equilibrium between these different oligomers is affected by pH, temperature and presence of mannose 6-phosphate residues. Each monomer forms a 9 stranded ß-barrel which can bind to a single mannose 6-phosphate residue.
Mannose 6-phosphate Binding
The CI-MPR and CD-MPR bind mannose 6-phosphate in a similar fashion. Both form a set of hydrogen bonds between key residues and characteristic hydroxyl groups on the mannose residue. Hydrogen bonds to hydroxyl groups at positions 2, 3 and 4 make the site specific for mannose alone.
Both MPRs share 4 residues that are essential for ligand binding. Mutation of any of these residues results in the loss of mannose 6-phosphate binding. These residues are glutamine, arginine, glutamic acid and tyrosine and are responsible for forming the hydrogen bonds that contact specific hydroxyl groups in the mannose residue.
- Type – hybrid or high mannose structures
- Presence of the phosphomonoester (mannose 6-phosphate) or phosphodiester (Man-phosphate-GlcNAc)
- Number of mannose 6-phosphate tags
- Location of the mannose 6-phosphate tag
The CI-MPR and CD-MPR are able to bind to this wide range of N-glycan structures by having a different binding site architecture. The MPRs also bind to the phosphate group in a slightly different manner. Domain 3 of the CI-MPR uses Ser-386 and an ordered water molecule to bind to the phosphate moiety. On the other hand the CD-MPR uses residues Asp-103, Asn-104 and His-105 to form favourable hydrogen bonds to the phosphate group. The CD-MPR also contains a divalent cation Mn2+ which forms favourable hydrogen bonds with the phosphate moiety.
CI-MPR and Cancer
It is well-established that the CI-MPR binds mannose 6-phosphate but there is a growing body of evidence that suggests the CI-MPR also binds to unglycosylated IGF-II. 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. IGF-II will then be targeted to the lysosome where it will be degraded. This regulates the level of free IGF-II in the body.
This function of the CI-MPR was determined through the use of knockout mice. It was observed that CI-MPR deficient mice had an increased level of free IGF-II and enlarged organs (around a 30% increase in size ). These mice die at day 15 of gestation due to cardiac hyperplasia. Death of the mice could be prevented when the IGF-II allele was also knocked out. When the CI-MPR and the IGF-II allele are knocked out we see a normal mouse as there is no longer a growth factor present that needs to be regulated.
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. Studies of multiple human cancers have shown that a loss of the CI-MPR function is associated with a progression in tumourigenesis. Loss of heterozygosity (LOH) at the CI-MPR locus has been displayed in multiple cancer types including liver and breast. However this is a relatively new concept and many more studies will have to investigate the relationship between the CI-MPR and cancer.
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- Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler M (2009). "P-type Lectins". Essentials of glycobiology (2nd ed.). Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press. ISBN 0879697709.
- Hoflack, B., Komfeld, S. (1985). "Lysosomal enzyme binding to mouse P388D1 macrophage membranes lacking the 215 kDa mannose 6-phosphate receptor: evidence for the existence of a second mannose 6-phosphate receptor". Proc. Natl. Acad. Sci. 82: 4428–32. doi:10.1073/pnas.82.13.4428. PMC 391114. PMID 3160044.
- Hoflack B, Kornfeld S (1985). "Purification and characterisation of a cation-dependent mannose 6-phosphate receptor from murine P388D1 macrophages and bovine liver". J. Biol. Chem. 260 (22): 12008–14. PMID 2931431.
- Reitman ML, Kornfeld S (1981). "Lysosomal enzymes targeting. N-Acetylglucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes". J. Biol. Chem. 256 (23): 11977–80. PMID 6457829.
- Duncan JR, Kornfeld S (March 1988). "Intracellular movement of two mannose 6-phosphate receptors: return to the Golgi apparatus". J. Cell Biol. 106 (3): 617–28. doi:10.1083/jcb.106.3.617. PMC 2115106. PMID 2964450.
- Le Borgne R, Hoflack B (1997). "Mannose 6-phosphate receptors regulate the formation of clathrin-coated vesicles in the TGN". J. Cell Biol. 137 (2): 335–45. doi:10.1083/jcb.137.2.335. PMC 2139777. PMID 9128246.
- Ghosh P, Dahms NM, Kornfeld S (2003). "Mannose 6-phosphate receptors: New twists in the tale.". Nature Reviews Molecular Cell Biology 4 (3): 202–212. doi:10.1038/nrm1050. PMID 12612639.
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- Johnson KF, Chan W, Kornfeld S (1990). "Cation-dependent mannose 6-phosphate receptor contains two internalisation signal in its cytoplasmic domain". Proc. Natl. Acad. Sci. 87: 10010–4. doi:10.1073/pnas.87.24.10010. PMC 55304. PMID 2175900.
- Bohnsack RN, Song X, Olson LJ, Kudo M, Gotschall RR, Canfield WM, Cummings RD, Smith DF, Dahms NM (2009). "Cation-independent Mannose 6-phosphate Receptor A Composite of Distinct Phosphomannosyl Binding Sites". Journal of Biological Chemistry 284 (50): 35215–35226. doi:10.1074/jbc.M109.056184. PMC 2787381. PMID 19840944.
- Tong PY, Kornfeld S (1989). "Ligand interactions of the cation-dependent mannose 6-phosphate receptor. Comparison with the cation-independent mannose 6-phosphate receptor". J. Biol. Chem. 264 (14): 7970–5. PMID 2542255.
- De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL (1996). "M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity". Nat. Genet. 11 (4): 447–9. doi:10.1038/ng1295-447. PMID 7493029.
- De Souza AT, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL (1995). "Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors". Oncogene 10 (9): 1725–9. PMID 7753549.
- Duncan JR, Kornfeld S (1988). "Intracellular movement of two mannose 6-phosphate receptors: return to the Golgi apparatus". J. Cell. Biol. 106: 617–28. doi:10.1083/jcb.106.3.617. PMC 2115106. PMID 2964450.
- Junghans U, Waheed A, von Figura K (1988). "The 'cation-dependent' mannose 6-phosphate receptor binds ligands in the absence of divalent cations". FEBS Left 237 (1-2): 81–4. doi:10.1016/0014-5793(88)80176-5. PMID 2971570.
- Hawkes C, Kar S (2004). "The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system". Brain Res. Brain Res. Rev. 44 (2–3): 117–40. doi:10.1016/j.brainresrev.2003.11.002. PMID 15003389.
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- Imperial College Lectins Research Information
- UniProtKB/ Swiss-Prot entry for the human cation-independent mannose 6-phosphate receptor
- UniProtKB/ Swiss-Prot entry for the human cation-dependent mannose 6-phosphate receptor
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Cation-independent mannose-6-phosphate receptor repeat Provide feedback
The cation-independent mannose-6-phosphate receptor contains 15 copies of a repeat.
Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ; , Nature 1987;329:301-307.: Insulin-like growth factor II receptor as a multifunctional binding protein. PUBMED:2957598 EPMC:2957598
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000479The cation-independent mannose-6-phosphate receptor is a type I membrane protein responsible for transport of phosphorylated lysosomal enzymes from the golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds insulin growth factor. It contains 15 copies of a repeat.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||integral to membrane (GO:0016021)|
|Molecular function||transporter activity (GO:0005215)|
|Biological process||transport (GO:0006810)|
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|Seed source:||Pfam-B_764 (release 3.0)|
|Number in seed:||12|
|Number in full:||1464|
|Average length of the domain:||136.00 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||77.56 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CIMR domain has been found. There are 57 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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