Alternative titles; symbols
HGNC Approved Gene Symbol: DMTN
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,048,931-22,082,525 (from NCBI)
Dematin, or EPB49, is an actin-bundling protein originally identified in the erythroid membrane skeleton. Its actin-bundling activity is abolished upon phosphorylation by cAMP-dependent protein kinase and is restored after dephosphorylation (Rana et al., 1993).
Chishti et al. (1989) proposed the name dematin (from the Greek 'dema,' a bundle) for an actin-bundling protein identified in the human erythroid membrane skeleton. Rana et al. (1993) noted that dematin consists of 2 polypeptide chains of 48 and 52 kD that were identified as protein 4.9 on SDS-polyacrylamide gels. In solution, dematin exists as a trimer and bundles actin filaments in a phosphorylation-dependent manner. Rana et al. (1993) cloned dematin from a human reticulocyte cDNA library. The deduced 383-amino acid protein has a calculated molecular mass of 43 kD. Dematin has a polyglutamine motif that may constitute a nuclear localization signal, a PEST sequence, a C-terminal domain highly similar to the C-terminal headpiece domain of villin (VIL; 193040), and several putative phosphorylation sites. Northern blot analysis detected variable dematin expression in all tissues examined. Immunofluorescence microscopy revealed punctate dematin staining around the cell nucleus in cultured human erythroblasts.
Although dematin is an actin-bundling protein of the erythroid membrane skeleton, it is abundantly expressed in human brain, heart, skeletal muscle, kidney, and lung. Azim et al. (1995) reported the primary structure of the 52-kD subunit of dematin, which differs from the 48-kD subunit by a 22-amino acid insertion within its headpiece domain. A unique feature of the insertion sequence of the 52-kD subunit is its homology to erythrocyte protein 4.2 (177070).
Rana et al. (1993) confirmed that purified human dematin possessed actin-bundling activity in vitro. Protease treatment and microsequencing revealed that the C-terminal headpiece domain bound actin filaments, but it did not have actin-bundling activity.
Azim et al. (1996) demonstrated that dematin and protein 4.2 bound ATP.
Gilligan and Bennett (1993) provided a review.
Using somatic cell hybrid panels and fluorescence in situ hybridization, Azim et al. (1995) localized the dematin gene to chromosome 8p21.1, a site distal to the locus of ankyrin (612641) at chromosome 8p11.2.
Peters et al. (1995) demonstrated that the murine dematin gene, symbolized Epb4.9, maps to chromosome 14. They raised the possibility that dematin mutations may be involved in neurologic abnormalities in the mouse.
By using homologous recombination in mouse embryonic stem cells, Khanna et al. (2002) deleted the headpiece domain of dematin to evaluate its function in vivo. Dematin headpiece-null mice were viable and born at the expected mendelian ratio. Hematologic evaluation showed evidence of compensated anemia and spherocytosis in these mice, however. The headpiece-null erythrocytes were osmotically fragile, and displayed reduced deformability and filterability. In vitro, significantly greater membrane fragmentation of these erythrocytes was demonstrated. Biochemical characterization showed a weakened membrane skeleton evidenced by reduced association of spectrin and actin to the plasma membrane. Together, these results provided evidence for the physiologic significance of dematin and demonstrated a role for the headpiece domain in the maintenance of structural integrity and mechanical properties of red cells in vivo.
Chen et al. (2007) created double-knockout mice lacking beta-adducin (ADD2; 102681) and the headpiece domain of dematin. Double-knockout pups were pale compared with wildtype pups, but otherwise they appeared grossly normal. Peripheral blood analysis showed severe hemolytic anemia with reduced number of erythrocytes/hematocrit/hemoglobin and an approximately 12-fold increase in the number of circulating reticulocytes. The presence of a variety of misshapen and fragmented erythrocytes correlated with increased osmotic fragility and reduced in vivo life span. Mutant erythrocyte membranes showed weak retention of spectrin-actin complexes, increased grain size, decreased filament number, and features consistent with the presence of large protein aggregates. Chen et al. (2007) concluded that dematin and adducin are essential for the maintenance of erythrocyte shape and membrane stability.
Azim, A. C., Knoll, J. H. M., Beggs, A. H., Chisti, A. H. Isoform cloning, actin binding, and chromosomal localization of human erythroid dematin, a member of the villin superfamily. J. Biol. Chem. 270: 17407-17413, 1995. [PubMed: 7615546] [Full Text: https://doi.org/10.1074/jbc.270.29.17407]
Azim, A. C., Marfatia, S. M., Korsgren, C., Dotimas, E., Cohen, C. M., Chishti, A. H. Human erythrocyte dematin and protein 4.2 (pallidin) are ATP binding proteins. Biochemistry 35: 3001-3006, 1996. [PubMed: 8608138] [Full Text: https://doi.org/10.1021/bi951745y]
Chen, H., Khan, A. A., Liu, F., Gilligan, D. M., Peters, L. L., Messick, J., Haschek-Hock, W. M., Li, X., Ostafin, A. E., Chishti, A. H. Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia. J. Biol. Chem. 282: 4124-4135, 2007. [PubMed: 17142833] [Full Text: https://doi.org/10.1074/jbc.M610231200]
Chishti, A. H., Faquin, W., Wu, C.-C., Branton, D. Purification of erythrocyte dematin (protein 4.9) reveals an endogenous protein kinase that modulates actin-bundling activity. J. Biol. Chem. 264: 8985-8991, 1989. [PubMed: 2722813]
Gilligan, D. M., Bennett, V. The junctional complex of the membrane skeleton. Semin. Hemat. 30: 74-83, 1993. [PubMed: 8434261]
Khanna, R., Chang, S. H., Andrabi, S., Azam, M., Kim, A., Rivera, A., Brugnara, C., Low, P. S., Liu, S.-C., Chishti, A. H. Headpiece domain of dematin is required for the stability of the erythrocyte membrane. Proc. Nat. Acad. Sci. 99: 6637-6642, 2002. [PubMed: 12011427] [Full Text: https://doi.org/10.1073/pnas.052155999]
Peters, L. L., Eicher, E. M., Azim, A. C., Chishti, A. H. The gene encoding the erythrocyte membrane skeleton protein dematin (Epb4.9) maps to mouse chromosome 14. Genomics 26: 634-635, 1995. [PubMed: 7607697] [Full Text: https://doi.org/10.1016/0888-7543(95)80192-o]
Rana, A. P., Ruff, P., Maalouf, G. J., Speicher, D. W., Chishti, A. H. Cloning of human erythroid dematin reveals another member of the villin family. Proc. Nat. Acad. Sci. 90: 6651-6655, 1993. [PubMed: 8341682] [Full Text: https://doi.org/10.1073/pnas.90.14.6651]