Disease relevance of TMOD1

• An intact coiled coil at the N terminus of the TMs is essential for Tmod binding, as modifications that disrupt the N-terminal helix, such as removal of the N-terminal acetyl group from AcTM1aZip or striated muscle alpha-TM, or introduction of a mutation that causes nemaline myopathy, Met-8-Arg, into AcTM1aZip destroyed Tmod binding [1].
• Human tropomodulin and a 64-kDa autoantigen in Graves disease (1D) are related: tropomodulin has 42 and 41% identity with the Graves protein in the N-terminal (69 residue) and C-terminal (194 residue) regions, respectively [2].
• To evaluate the tissue-specific expression pattern of the 64kD human autoantigen D1, a tropomodulin-related protein that may be involved in thyroid-associated ophthalmopathy [3].

High impact information on TMOD1

• Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart [4].
• Tropomodulin caps the slow-growing, pointed filament ends in muscle and in erythrocytes [5].
• We describe here a previously uncharacterized tropomodulin (Tmod) isoform, Tmod3, which is widely expressed in human tissues and is present in human microvascular endothelial cells (HMEC-1) [6].
• Tropomodulin caps the pointed ends of actin filaments [7].
• We propose that tropomodulin plays a role in maintaining the narrow length distributions of the stable, tropomyosin-containing actin filaments in striated muscle and in red blood cells [7].

Biological context of TMOD1

• Results also suggest tropomodulin has a groove-type, rather than a cavity-type, binding site for hTM5 [8].
• We further characterized the tropomodulin-binding site by creating a series of deletion and missense mutations within this region, followed by a solid-phase binding assay [8].
• Nine independent PCR clones, five from a human reticulocyte cDNA library and four from the fetal liver cDNA library, revealed identical N-terminal 103 amino acids, suggesting that the sequence reported here may also be of erythrocyte tropomodulin [9].
• The tropomodulin gene was assigned to human chromosome 9q22.2-q22.3, a region that is also known to contain several other genes and disease loci and is proximal to the loci for gelsolin and alpha-fodrin [2].
• The N-terminal "KRK ring" may participate in balancing electrostatic force with hydrophobic interaction in dimerization of TM and its binding to E-Tmod [10].

Anatomical context of TMOD1

• These data provide evidence that Tmod and nebulin may work together as a linked mechanism to control thin filament lengths in skeletal muscle [11].
• Tropomodulin is a globular protein that caps the pointed end of actin filaments by complexing with the N-terminus of a tropomyosin (TM) molecule [8].
• In myofibrils, tropomodulin has been localized at or near the free end of thin filaments [12].
• Tropomodulin is highly concentrated at the postsynaptic domain of human and rat neuromuscular junctions [13].
• Tropomodulin is expressed in skeletal muscle and recent studies suggest that tropomodulin is associated with synaptic membranes [13].

Associations of TMOD1 with chemical compounds

• The N-terminal end of nebulin interacts with tropomodulin at the pointed ends of the thin filaments [11].
• Leucine 135 of tropomodulin-1 regulates its association with tropomyosin, its cellular localization, and the integrity of sarcomeres [14].
• Glutathione S-transferase affinity chromatography and immunoprecipitation assays reveal that Tmod sense mutations of either amino acid 134, 135, or 136 causes various degrees of loss of function of Tmod TM-binding ability [14].
• Mechanical disruption of the lens fiber cell membrane skeleton releases tropomodulin and actin-containing oligomeric complexes that can be isolated by gel filtration column chromatography, sucrose gradient centrifugation and immunoadsorption [15].
• Tropomodulin binding to tropomyosins. Isoform-specific differences in affinity and stoichiometry [16].

Physical interactions of TMOD1

• Erythrocyte tropomodulin binds to the N-terminus of hTM5, a tropomyosin isoform encoded by the gamma-tropomyosin gene [12].

Co-localisations of TMOD1

• Immunofluorescence microscopy revealed that the N-terminal end of nebulin colocalizes with Tmod at the pointed ends of thin filaments [11].

Other interactions of TMOD1

• Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin [12].
• Tropomodulin labeling also colocalizes with desmin and beta-amyloid proteins which are concentrated in the postsynaptic region [13].
• The insertion of several homologous repeats in the midsection of the Graves protein, together with the extension of a proline-rich C terminus, accounts for the differences in length between the Graves protein (572 residues) and tropomodulin (359 residues) [2].
• Among the potentially relevant genes, PIP 5K1C, VIP, tropomodulin, and MMP2 encoded mediators known to influence outflow resistance [17].
• The distribution of actin filaments is regulated by the binding of end-binding proteins, including capping protein (CapZ in muscle), the Arp2/3 complex, gelsolin, formin and tropomodulin, to the end of the actin filament [18].

Analytical, diagnostic and therapeutic context of TMOD1

• Molecular cloning and characterization of human fetal liver tropomodulin. A tropomyosin-binding protein [9].
• In addition to negative staining, immunogold labelling for tropomodulin at the sites of the central junctions was also visualized by a quick-freeze, deep-etch, rotary-replication technique [19].
• In this present study, circular dichroism was used to study the interaction of two designed chimeric proteins, AcTM1aZip and AcTM1bZip, containing the N terminus of a long or a short TM, respectively, with protein fragments containing residues 1 to 130 of erythrocyte or skeletal muscle Tmod [1].
• A 1.9-kb human tropomodulin cDNA clone was used to map its gene by fluorescence in situ hybridization [2].
• Immunoblotting of supernatants and pellets obtained after extraction of myosin from myofibrils also indicates that tropomodulin remains associated with the thin filaments [20].

References