Alternative titles; symbols
HGNC Approved Gene Symbol: PRG2
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38) : 11:57,386,780-57,390,650 (from NCBI)
Eosinophil granule major basic protein (MBP) comprises the crystalloid core of the eosinophil granule. Wasmoen et al. (1988) and Weller et al. (1988) published a partial amino acid sequence for MBP, also designated proteoglycan-2 (PRG2). Using this partial sequence, Barker et al. (1988) isolated a full-length PRG2 cDNA from a human promyelocytic leukemia cell line (HL60) cDNA library. McGrogan et al. (1988) independently isolated a PRG2 cDNA from an HL60 cell line cDNA. Yoshimatsu et al. (1992) also identified PRG2 in a search for a natural killer (NK) cell-activating factor purified from the supernatant of a T-cell hybridoma.
McGrogan et al. (1988) and Barker et al. (1988) determined that the PRG2 cDNA encodes a deduced 222-amino acid protein with a 15-amino acid hydrophobic signal sequence. PRG2 is initially translated as a 25-kD preproprotein that is posttranslationally modified to a proprotein. Posttranslational modification results in the mature form of PRG2, which is encoded by the carboxy 117 amino acids of the preproprotein and has a molecular mass of 14 kD. The 90-amino acid N-terminal domain has 1 potential N-linked glycosylation site. Yoshimatsu et al. (1992) reported that the C-terminal end of PRG2 shares homology with animal lectins.
McGrogan et al. (1988) determined that the putative PRG2 proprotein, also known as proMBP, is a bipolar molecule. The amino-terminal half is hydrophilic, whereas the mature PRG2 is hydrophobic. Barker et al. (1988) hypothesized that the translation of PRG2 as a bipolar proprotein may mask the toxic effects of the mature PRG2 and protect the eosinophil from damage while the protein is processed through the endoplasmic reticulum to its sequestered site in the eosinophil granule.
Using Northern blot analysis, McGrogan et al. (1988) detected a major 1-kb transcript and a minor 0.5-kb PRG2 transcript in HL60 cells. By the same method, Li et al. (1995) detected a 1-kb transcript in immature cells including bone-marrow and HL60 cells, but not in purified blood eosinophils. Using RT-PCR, Li et al. (1995) detected an additional 1.6-kb transcript in bone marrow cells and HL60 cells at lower levels than the 1-kb transcript. In differentiated blood eosinophils from idiopathic hypereosinophilic syndrome patients, the 1.6-kb transcript predominated.
Li et al. (1995) isolated genomic clones of PRG2 and determined that PRG2 is contains 14 exons spanning 35 kb, with 5 coding exons (exons 10-14). After comparing cDNA and genomic clones, Li et al. (1995) hypothesized that the 2 PRG2 transcripts originate from alternatively spliced variants that differ in the 5-prime untranslated region. The 1-kb transcript is derived from exons 9-14. The 1.6-kb transcript is derived from exons 1-8 and 10-14. Li et al. (1995) hypothesized that promoter switching may occur during eosinophil differentiation and may be used to reduce protein synthesis. Once the mature PRG2 is stably stored in granules, terminally differentiated eosinophils may reduce their PRG2 expression by switching promoters.
Consistent with the hypothesized function of PRG2 as a cytotoxic polypeptide, McGrogan et al. (1988) found that PRG2 has microbicidal activity against gram-negative and gram-positive bacteria and fungi. Yoshimatsu et al. (1992) demonstrated that PRG2 enhanced natural killer cell activity. PRG2 also enhanced the activity of killer T cells induced by the mixed lymphocyte tumor cell reaction.
Oxvig et al. (1993) analyzed tryptic peptides from circulating pregnancy-associated plasma protein-A (PAPPA; 176385) and found sequences that exactly matched 3 predicted tryptic peptides from proMBP, suggesting that proMBP is a constituent of circulating PAPPA. Sequence analysis and denaturing gel chromatography of PAPPA/proMBP confirmed the finding. Oxvig et al. (1993) concluded that circulating PAPPA is a disulfide-bridged complex with proMBP in which the subunits of the constituents are present in a 1:1 molar ratio.
Overgaard et al. (2000) compared the proteolytic activity of recombinant PAPPA and pregnancy serum PAPPA/proMBP complex and observed a greater than 100-fold difference, showing that proMBP functions as a proteinase inhibitor in vivo. Pregnancy serum and plasma were found to contain traces (less than 1%) of uncomplexed PAPPA with a much higher specific activity than the PAPPA/proMBP complex, suggesting that the measurable activity of the PAPPA/proMBP complex probably results from the presence of a minor subpopulation of partly inhibited PAPPA that exists in a 2:1 complex with proMBP. Overgaard et al. (2000) stated that inhibition of PAPPA by proMBP represented a novel inhibitory mechanism with the enzyme irreversibly bound to its inhibitor by disulfide bonds.
The International Radiation Hybrid Mapping Consortium mapped the PRG2 gene to chromosome 11 (A005W41). By FISH, Plager et al. (2001) mapped the PRG2 and PRG3 (606814) genes to chromosome 11cen-q12.
Barker, R. L., Gleich, G. J., Pease, L. R. Acidic precursor revealed in human eosinophil granule major basic protein cDNA. J. Exp. Med. 168: 1493-1498, 1988. Note: Erratum: J. Exp. Med. 170: 1057 only, 1989. [PubMed: 3171483] [Full Text: https://doi.org/10.1084/jem.168.4.1493]
Li, M.-S., Sun, L., Satoh, T., Fisher, L. M., Spry, C. J. F. Human eosinophil major basic protein, a mediator of allergic inflammation, is expressed by alternative splicing from two promoters. Biochem. J. 305: 921-927, 1995. [PubMed: 7531438] [Full Text: https://doi.org/10.1042/bj3050921]
McGrogan, M., Simonsen, C., Scott, R., Griffith, J., Ellis, N., Kennedy, J., Campanelli, D., Nathan, C., Gabay, J. Isolation of a complementary DNA clone encoding a precursor to human eosinophil major basic protein. J. Exp. Med. 168: 2295-2308, 1988. [PubMed: 3199069] [Full Text: https://doi.org/10.1084/jem.168.6.2295]
Overgaard, M. T., Haaning, J., Boldt, H. B., Olsen, I. M., Laursen, L. S., Christiansen, M., Gleich, G. J., Sottrup-Jensen, L., Conover, C. A., Oxvig, C. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J. Biol. Chem. 275: 31128-31133, 2000. [PubMed: 10913121] [Full Text: https://doi.org/10.1074/jbc.M001384200]
Oxvig, C., Sand, O., Kristensen, T., Gleich, G. J., Sottrup-Jensen, L. Circulating human pregnancy-associated plasma protein-A is disulfide-bridged to the proform of eosinophil major basic protein. J. Biol. Chem. 268: 12243-12246, 1993. [PubMed: 7685339]
Plager, D. A., Weiler, D. A., Loegering, D. A., Johnson, W. B., Haley, L., Eddy, R. L., Shows, T. B., Gleich, G. J. Comparative structure, proximal promoter elements, and chromosome location of the human eosinophil major basic protein genes. Genomics 71: 271-281, 2001. [PubMed: 11170744] [Full Text: https://doi.org/10.1006/geno.2000.6391]
Wasmoen, T. L., Bell, M. P., Loegering, D. A., Gleich, G. J., Prendergast, F. G., McKean, D. J. Biochemical and amino acid sequence analysis of human eosinophil granule major basic protein. J. Biol. Chem. 263: 12559-12563, 1988. [PubMed: 3410852]
Weller, P. F., Ackerman, S. J., Smith, J. A. Eosinophil granule proteins: major basic protein is distinct from the smaller subunit of eosinophil peroxidase. J. Leukoc. Biol. 43: 1-4, 1988. [PubMed: 3422083] [Full Text: https://doi.org/10.1002/jlb.43.1.1]
Yoshimatsu, K., Ohya, Y., Shikata, Y., Seto, T., Hasegawa, Y., Tanaka, I., Kawamura, T., Kitoh, K., Toyoshima, S., Osawa, T. Purification and cDNA cloning of a novel factor produced by a human T-cell hybridoma: sequence homology with animal lectins. Molec. Immun. 29: 537-546, 1992. [PubMed: 1565101] [Full Text: https://doi.org/10.1016/0161-5890(92)90012-m]