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 [1].
• Immunoblotting of supernatants and pellets obtained after extraction of myosin from myofibrils also indicates that tropomodulin remains associated with the thin filaments [2].
• Tropomodulin is a new, 40.6-kD tropomyosin-binding protein from the human erythrocyte membrane skeleton that binds to one end of erythrocyte tropomyosin and blocks head-to-tail association of tropomyosin molecules along actin filaments [2].
• Here we show that rat psoas skeletal muscle contains tropomodulin based on immunoreactivity, identical apparent mobility on SDS gels, and ability to bind muscle tropomyosin [2].
• Tropomodulin is a 40.6-kD protein that colocalizes with actin filament pointed ends in skeletal muscle [3].

Biological context of Tmod1

• N-tropomodulin: a novel isoform of tropomodulin identified as the major binding protein to brain tropomyosin [4].
• Comparisons of wild-type Tmod and Tmod carrying mutations in these peptide domains revealed that Tmod normally traffics through the nucleus [5].
• We unexpectedly discovered significant levels of Tmod in nuclei and then defined peptide domains in Tmod responsible for nuclear import and export [5].
• We propose that this is due to the low affinity of tropomodulin for pointed ends (K(d) approximately 0.3 microM), which allows tropomodulin to rapidly exchange binding sites and transiently block access of actin monomers to all pointed ends [6].
• The deduced amino acid sequence contains four distinct structural regions, an RGD motif, a leucine-rich repeat (LRR) region, a tropomodulin domain, and a proline-rich domain [7].

Anatomical context of Tmod1

• Peptide sequencing as well as immunoblotting showed that one of the two proteins is identical to tropomodulin, a tropomyosin-binding protein originally identified in erythrocytes [4].
• Tropomodulin (Tmod) is a cytoskeletal actin-capping protein that interacts with tropomyosin at the pointed end of actin filaments [5].
• E-Tmod is an isoform that expresses predominantly in cardiac cells and slow skeletal muscle fibers [5].
• 1.2-1.6 copies of muscle tropomodulin are present per thin filament in myofibrils, supporting the possibility that one or two tropomodulin molecules may be associated with the two terminal tropomyosin molecules at the pointed end of each thin filament [2].
• Tropomodulin in rat cardiac muscle. Localization of protein is independent of messenger RNA distribution during myofibrillar development [3].

Associations of Tmod1 with chemical compounds

• Indirect immunofluorescence staining of 5 microns cryosections of adult rat lens reveals that both tropomodulin and tropomyosin colocalize with rhodamine phalloidin staining for actin filaments on fiber cell plasma membranes [8].
• For example, lens tropomodulin binds tropomyosin in a solid-phase blot binding assay, and extraction experiments with Triton X-100, urea and NaOH show that the membrane-bound tropomodulin in the lens is a tightly associated peripheral membrane protein that is a component of the Triton-insoluble cytoskeleton [8].
• Identification, expression analysis and polymorphism of a novel RLTPR gene encoding a RGD motif, tropomodulin domain and proline/leucine-rich regions [7].
• Tropomodulin mRNA increases in the dentate gyrus of the hippocampus following prolonged seizure activity induced by kainic acid administration; the increase is clearly evident 8 h after initiation of seizures and is still present 1 week later [9].

Analytical, diagnostic and therapeutic context of Tmod1

• Northern blotting and RNase protection assays as well as immunoblotting showed that N-tropomodulin is expressed predominantly in brain [4].
• Immunofluorescence of primary frontal cortex cell cultures showed that N-tropomodulin is specifically expressed in neurons [4].
• Sequence analysis of the cDNA clone revealed this protein to be a novel isoform of tropomodulin which is the product of a distinct gene, and is herein referred to as N-tropomodulin [4].
• Fluorescent in situ hybridization experiments using tropomodulin cDNA probe in cardiocytes that have been cultured for 3 to 5 days show a distribution of large mRNA patches [3].
• We have used immunoblot and immunoprecipitation analyses, as well as immunofluorescence localization to identify and characterize two additional components of the membrane skeleton in the rat lens: tropomyosin and the tropomyosin-binding protein tropomodulin [8].

References