Alternative titles; symbols
HGNC Approved Gene Symbol: M6PR
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:8,940,361-8,949,645 (from NCBI)
Both mannose 6-phosphate receptors (MPRs; M6PR and MPRI, 147280) mediate recruitment of the lysosomal hydrolases to clathrin-coated areas of the trans-Golgi network, from which carrier vesicles deliver the MPR-hydrolase complexes to endosomes (summary by Puertollano et al., 2001).
Ludwig et al. (1992) cloned the cation-dependent mannose 6-phosphate receptor in the mouse and also a very unusual pseudogene corresponding to it. Although promoter elements in the 5-prime region upstream of the transcription-initiation site resemble those contained in genes constitutively transcribed, Northern blot analysis demonstrated that the gene is variably expressed in adult mouse tissues and during mouse development.
Pseudogene
Ludwig et al. (1992) cloned a M6pr pseudogene in mouse. The pseudogene, which was flanked by direct repeats, was almost colinear with the cDNA, indicating that it presumably arose by reverse transcription of an mRNA. The pseudogene differs from the cDNA in 2 respects. At its 5-prime end, the pseudogene contained an additional 340-nucleotide sequence homologous to the promoter region of the functional gene. This sequence exhibited some promoter activity in vitro. Furthermore, in the pseudogene, a 24-nucleotide insertion interrupted the region homologous to the 5-prime noncoding region of the cDNA. In the functional gene, this 24-nucleotide sequence occurred between exons 1 and 2 where it was flanked by typical consensus sequences of exon/intron boundaries. Therefore, it may represent an additional exon of the functional gene. Ludwig et al. (1992) suggested that expression of the M6PR gene in the mouse may be regulated by use of different promoters and/or alternative splicing.
In the mouse, Ludwig et al. (1992) determined that the M6pr gene is present in 1 copy per haploid genome. The M6pr gene has a genomic length of 10 kb and contains 7 exons. Exon 1 encodes the 5-prime untranslated portion of the mRNA, whereas exons 2-7 encode the luminal, transmembrane, and cytoplasmic domains. Exon 7 also contains a 1.2-kb 3-prime untranslated region of the mRNA. The promoter elements in the 5-prime region upstream of the transcription-initiation site resemble those contained in genes constitutively transcribed.
Dahms et al. (1987) and Pohlmann et al. (1987) demonstrated by use of cDNA clones in an analysis of a panel of somatic cell hybrids that the gene for the cation-dependent receptor is located on human chromosome 12.
Ludwig et al. (1992) mapped the M6pr gene to chromosome 6 of the mouse. Ludwig et al. (1992) mapped the mouse pseudogene to chromosome 3.
Watanabe et al. (1990) studied the function of SMPR in transfected mouse L cells that do not express the larger insulin-like growth factor II/mannose 6-phosphate receptor. The findings indicate that SMPR has a role in sorting of newly synthesized lysosomal enzyme.
The cation-independent (147280) and cation-dependent forms of mannose-6-phosphate receptors are known as MPR46 and MPR300, respectively, on the basis of their molecular size. Both mediate targeting of Man-6-P-containing lysosomal proteins to lysosomes. Pohlmann et al. (1995) studied the contribution of either or both MPRs to the transport of lysosomal proteins by the study of fibroblasts from mouse embryos that were homozygous for disrupted alleles of either MPR46 or MPR300 or both. Fibroblasts missing both MPRs secreted most of the newly synthesized lysosomal proteins and were unable to maintain the catabolic function of lysosomes. As a result, the intracellular levels of lysosomal proteins decreased to less than 20%, and undigested material accumulated in the lysosomal compartment. Fibroblasts lacking either MPR exhibited only a partial missorting and maintained, in general, half-normal to normal levels of lysosomal proteins. The same species of lysosomal proteins were found in secretions of double MPR-deficient fibroblasts as in secretions of single MPR-deficient fibroblasts, but at different ratios. This indicated to the authors that neither MPR has an exclusive affinity for one or several lysosomal proteins. Furthermore, neither MPR could substitute in vivo for the loss of the other. Pohlmann et al. (1995) proposed that the heterogeneity of the Man-6-P recognition marker within a lysosomal protein and among different lysosomal proteins has necessitated the evolution of 2 MPRs with complementary binding properties to ensure an efficient targeting of lysosomal proteins.
The cytosolic tails of both the cation-independent and the cation-dependent mannose-6-phosphate receptors contain acidic cluster-dileucine signals that direct sorting from the trans-Golgi network to the endosomal-lysosomal system. Puertollano et al. (2001) found that these signals bind to the VHS domain of the Golgi-localized, gamma-ear-containing, ARF-binding proteins (GGA1, 606004; GGA2, 606005; GGA3, 606006). The receptors and the GGAs left the trans-Golgi network on the same tubulovesicular carriers. A dominant-negative GGA mutant blocked exit of the receptors from the trans-Golgi network. Thus, Puertollano et al. (2001) concluded that the GGAs appear to mediate sorting of the mannose-6-phosphate receptors to the trans-Golgi network.
Roberts et al. (1998) reported the 3-dimensional structure of a glycosylation-deficient, yet fully functional form of the extracytoplasmic domain of the bovine cation-dependent MPR (residues 3 to 154) complexed with mannose-6-phosphate at 1.8-angstrom resolution. The extracytoplasmic domain of the cation-dependent MPR crystallized as a dimer, and each monomer folded into a 9-stranded flattened beta barrel, which bears a striking resemblance to avidin. The distance of 40 angstroms between the 2 ligand-binding sites of the dimer provides a structural basis for the observed differences in binding affinity exhibited by the cation-dependent MPR toward various lysosomal enzymes.
Receptors specific for phosphomannosyl residues play a critical role in the segregation and targeting of lysosomal enzymes to lysosomes. Since lysosomal enzymes share a common site of synthesis with both membrane and secretory proteins in the rough endoplasmic reticulum, they must be sorted from these other proteins in order to be specifically delivered to lysosomes. This specific transport is accomplished by the generation of mannose 6-phosphate (M6P) recognition markers on the lysosomal enzymes which then bind specifically to mannose 6-phosphate receptors located in the Golgi apparatus; the receptor-ligand complex is then translocated via vesicles to a prelysosomal compartment where the low pH stimulates dissociation. Two distinct mannose 6-phosphate receptors have been identified: one is cation-independent (147280) and has an apparent molecular weight of 215,000. The second, the cation-dependent mannose 6-phosphate receptor, or small mannose 6-phosphate receptor (SMPR), has an apparent molecular weight of only 46,000 and requires divalent cations for high-affinity binding with its ligand (summary by Dahms et al., 1987). The 2 receptors are immunologically unrelated, and sequence analysis indicated no homology (Pohlmann et al., 1987).
Dahms, N. M., Lobel, P., Breitmeyer, J., Chirgwin, J. M., Kornfeld, S. 46 kd mannose 6-phosphate receptor: cloning, expression, and homology to the 215 kd mannose 6-phosphate receptor. Cell 50: 181-192, 1987. [PubMed: 2954652] [Full Text: https://doi.org/10.1016/0092-8674(87)90214-5]
Ludwig, T., Ruther, U., Metzger, R., Copeland, N. G., Jenkins, N. A., Lobel, P., Hoflack, B. Gene and pseudogene of the mouse cation-dependent mannose 6-phosphate receptor: genomic organization, expression, and chromosomal localization. J. Biol. Chem. 267: 12211-12219, 1992. [PubMed: 1376319]
Pohlmann, R., Boeker, M. W. C., von Figura, K. The two mannose 6-phosphate receptors transport distinct complements of lysosomal proteins. J. Biol. Chem. 270: 27311-27318, 1995. [PubMed: 7592993] [Full Text: https://doi.org/10.1074/jbc.270.45.27311]
Pohlmann, R., Nagel, G., Schmidt, B., Stein, M., Lorkowski, G., Krentler, C., Cully, J., Meyer, H. E., Grzeschik, K.-H., Mersmann, G., Hasilik, A., von Figura, K. Cloning of a cDNA encoding the human cation-dependent mannose 6-phosphate-specific receptor. Proc. Nat. Acad. Sci. 84: 5575-5579, 1987. [PubMed: 2441386] [Full Text: https://doi.org/10.1073/pnas.84.16.5575]
Puertollano, R., Aguilar, R. C., Gorshkova, I., Crouch, R. J., Bonifacino, J. S. Sorting of mannose 6-phosphate receptors mediated by the GGAs. Science 292: 1712-1716, 2001. [PubMed: 11387475] [Full Text: https://doi.org/10.1126/science.1060750]
Roberts, D. L., Weix, D. J., Dahms, N. M., Kim, J.-J. P. Molecular basis of lysosomal enzyme recognition: three-dimensional structure of the cation-dependent mannose 6-phosphate receptor. Cell 93: 639-648, 1998. [PubMed: 9604938] [Full Text: https://doi.org/10.1016/s0092-8674(00)81192-7]
Watanabe, H., Grubb, J. H., Sly, W. S. The overexpressed human 46-kDa mannose 6-phosphate receptor mediates endocytosis and sorting of beta-glucuronidase. Proc. Nat. Acad. Sci. 87: 8036-8040, 1990. [PubMed: 2172972] [Full Text: https://doi.org/10.1073/pnas.87.20.8036]