Alternative titles; symbols
HGNC Approved Gene Symbol: TMOD1
Cytogenetic location: 9q22.33 Genomic coordinates (GRCh38): 9:97,501,180-97,601,743 (from NCBI)
Sung et al. (1991, 1992) cloned the tropomodulin gene from human reticulocyte and fetal liver cDNA libraries.
By Northern blot analysis, Sung et al. (1996) showed that the TMOD gene is expressed in major human tissues at different levels in the following order: heart and skeletal muscle much greater than in brain, lung, and pancreas, which is greater than in placenta, liver, and kidney. They pointed to structural similarities between tropomodulin and the 64-kD autoantigen in Graves disease (139080) and suggested that the 2 genes evolved from a common ancestral gene.
Chu et al. (2000) noted that erythrocyte TMOD is a 359-amino acid globular protein.
By RNA dot blot analysis, Conley et al. (2001) confirmed expression of ETMOD in almost every tissue tested, with highest abundance in fetal and adult heart and skeletal muscle.
Human erythrocyte tropomodulin is a 43-kD tropomyosin-regulating protein (Gilligan and Bennett, 1993). It may modulate the association of tropomyosin with the spectrin-actin complex in the erythrocyte membrane skeleton, and thus the viscoelastic properties of erythrocytes.
Tropomodulin is associated with the pointed end of the actin filaments (Fowler et al., 1993). Sung et al. (1996) stated that it binds specifically to the N terminus of tropomyosin and blocks the elongation and depolarization of tropomyosin-coated actin filaments.
Conley (2001) found that both Tmod and Smlmod (LMOD1; 602715) cofractionated with tropomyosin in the Triton-insoluble cytoskeleton fraction of rabbit stomach smooth muscle, and both were solubilized by high salt. Immunofluorescent localization found Smlmod present along the length of actin filaments of rat intestinal smooth muscle, while Tmod stained in a punctate pattern distinct from that of actin filaments or the dense body marker, alpha-actinin (see 102575). Hypercontraction of rat intestinal smooth muscle with 10 mM Ca(2+) caused both Smlmod and Tmod to associate near alpha-actinin at the periphery of actin-rich contraction bands.
Using PCR methods to obtain TMOD genomic clones, Chu et al. (2000) determined that the TMOD gene contains 9 exons. Chu et al. (2000) suggested that the use of alternative promoters may account for tissue-specific expression and regulation.
Crystal Structure
Rao et al. (2014) described the crystal structures of actin complexes with the unstructured amino-terminal and the leucine-rich repeat carboxy-terminal domains of TMOD. The structures and biochemical analysis of structure-inspired mutants showed that 1 TMOD molecule interacts with 3 actin subunits at the pointed end, while also contacting 2 tropomyosin (see TPM1, 191010) molecules on each side of the filament. Rao et al. (2014) found that TMOD achieves high-affinity binding through several discrete low-affinity interactions, which suggested a mechanism for controlled subunit exchange at the pointed end.
Sung et al. (1991) mapped the TMOD gene to 9q22.2-q22.3 by in situ hybridization. By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Tmod gene to mouse chromosome 4, and White et al. (1995) used recombinant inbred strains to map the gene to a region within 1.0 cM of Mup1 (major urinary protein-1) on chromosome 4.
Lench et al. (1996) created an EST- and STS-based YAC contig map of 9q22.3 and showed that it contains the following genes in this order (from centromere to telomere): TMOD, XPA (611153), ALDOB (612724), BAAT (602938). All 4 of these genes map to a syntenic region of mouse chromosome 4 and are situated in the same order as their counterparts on human 9q22.3.
Chu, X., Thompson, D., Yee, L. J., Sung, L. A. Genomic organization of mouse and human erythrocyte tropomodulin genes encoding the pointed end capping protein for the actin filaments. Gene 256: 271-281, 2000. [PubMed: 11054557] [Full Text: https://doi.org/10.1016/s0378-1119(00)00327-9]
Conley, C. A., Fritz-Six, K. L., Almenar-Queralt, A., Fowler, V. M. Leiomodins: larger members of the tropomodulin (Tmod) gene family. Genomics 73: 127-139, 2001. [PubMed: 11318603] [Full Text: https://doi.org/10.1006/geno.2000.6501]
Conley, C. A. Leiomodin and tropomodulin in smooth muscle. Am. J. Physiol. Cell Physiol. 280: C1645-C1656, 2001. [PubMed: 11350761] [Full Text: https://doi.org/10.1152/ajpcell.2001.280.6.C1645]
Fowler, V. M., Sussmann, M. A., Miller, P. G., Flucher, B. E., Daniels, M. P. Tropomodulin is associated with the free (pointed) ends of the thin filaments in rat skeletal muscle. J. Cell Biol. 120: 411-420, 1993. [PubMed: 8421055] [Full Text: https://doi.org/10.1083/jcb.120.2.411]
Gilligan, D. M., Bennett, V. The junctional complex of the membrane skeleton. Semin. Hemat. 30: 74-83, 1993. [PubMed: 8434261]
Lench, N. J., Telford, E. A., Andersen, S. E., Moynihan, T. P., Robinson, P. A., Markham, A. F. An EST and STS-based YAC contig map of human chromosome 9q22.3 Genomics 38: 199-205, 1996. [PubMed: 8954802] [Full Text: https://doi.org/10.1006/geno.1996.0616]
Pilz, A., Woodward, K., Povey, S., Abbott, C. Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25: 139-149, 1995. [PubMed: 7774911] [Full Text: https://doi.org/10.1016/0888-7543(95)80119-7]
Rao, J. N., Madasu, Y., Dominguez, R. Mechanism of actin filament pointed-end capping by tropomodulin. Science 345: 463-467, 2014. [PubMed: 25061212] [Full Text: https://doi.org/10.1126/science.1256159]
Sung, L. A., Fan, Y. S., Lambert, K., Fowler, V., Chien, S., Lin, C. Assignment of human erythrocyte tropomodulin gene to q22 of chromosome 9. (Abstract) Cytogenet. Cell Genet. 58: 1944, 1991.
Sung, L. A., Fan, Y.-S., Lin, C. C. Gene assignment, expression, and homology of human tropomodulin. Genomics 34: 92-96, 1996. [PubMed: 8661028] [Full Text: https://doi.org/10.1006/geno.1996.0245]
Sung, L. A., Fowler, V. M., Lambert, K., Chien, S. Molecular cloning of human erythroid tropomodulin. (Abstract) FASEB J. 5: A1625, 1991.
Sung, L. A., Fowler, V. M., Lambert, K., Sussman, M. A., Karr, D., Chien, S. Molecular cloning and characterization of human fetal liver tropomodulin: a tropomyosin-binding protein. J. Biol. Chem. 267: 2616-2621, 1992. [PubMed: 1370827]
White, R. A., Dowler, L. L., Woo, M., Adkison, L. R., Pal, S., Gershon, D., Fowler, V. M. The tropomodulin (Tmod) gene maps to chromosome 4, closely linked to Mup1. Mammalian Genome 6: 332-333, 1995. [PubMed: 7626883] [Full Text: https://doi.org/10.1007/BF00364795]