Polymorphism in tropomyosin structure and function

Janco, Miro; Suphamungmee, Worawit; Li, Xiaochuan; Lehman, William; Lehrer, Sherwin S.; Geeves, Michael A.

doi:10.1007/s10974-013-9353-x

Cited by 30 publications

(22 citation statements)

References 61 publications

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“…The motivation for development of the model has been the work from our group and others showing that mutations cause complex effects, often at a significant distance from the site of amino acid replacement (17)(18)(19)(20). The function of the thin filament as a regulatory agent relies on the ability of the individual protein components to interact dynamically in response to physiological demands.…”

Section: Resultsmentioning

confidence: 99%

Atomic resolution probe for allostery in the regulatory thin filament

Williams

Lehman

Tardiff

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Calcium binding and dissociation within the cardiac thin filament (CTF) is a fundamental regulator of normal contraction and relaxation. Although the disruption of this complex, allosterically mediated process has long been implicated in human disease, the precise atomiclevel mechanisms remain opaque, greatly hampering the development of novel targeted therapies. To address this question, we used a fully atomistic CTF model to test both Ca 2+ binding strength and the energy required to remove Ca 2+ from the N-lobe binding site in WT and mutant troponin complexes that have been linked to genetic cardiomyopathies. This computational approach is combined with measurements of in vitro Ca 2+ dissociation rates in fully reconstituted WT and cardiac troponin T R92L and R92W thin filaments. These human disease mutations represent known substitutions at the same residue, reside at a significant distance from the calcium binding site in cardiac troponin C, and do not affect either the binding pocket affinity or EF-hand structure of the binding domain. Both have been shown to have significantly different effects on cardiac function in vivo. We now show that these mutations independently alter the interaction between the Ca 2+ ion and cardiac troponin I subunit. This interaction is a previously unidentified mechanism, in which mutations in one protein of a complex indirectly affect a third via structural and dynamic changes in a second to yield a pathogenic change in thin filament function that results in mutation-specific disease states. We can now provide atom-level insight that is potentially highly actionable in drug design.cardiac thin filament | hypertrophic cardiomyopathy | calcium homeostasis | molecular modeling | steered molecular dynamics C ardiac contraction is regulated by the binding of Ca 2+ to cardiac troponin C (cTnC) (1, 2) ( Fig. 1). The Ca 2+ binds in an EF-hand motif, consisting of two α-helices separated by a loop region containing seven coordinating oxygens that interact with the Ca 2+ , as seen in Fig. 2. Once Ca 2+ is bound, interactions between cTnC and the switch peptide domain of cardiac troponin I (cTnI) cause conformational changes that reduce the ability of cTnI to bind to actin (3). When bound to actin, cTnI shifts the equilibrium location of cardiac tropomyosin (cTM) to a position that prevents the interaction of actin with myosin, thereby inhibiting the power stroke that drives contraction of cardiac muscle (4, 5). Thus, Ca 2+ binding can be viewed as the initial step in a process that results in the eventual hydrolysis of ATP, with the sliding of the thin filament over the thick filament and the generation of mechanical work (5, 6). In disease states, changes in the ability of the cardiac muscle to be properly regulated by and to regulate Ca 2+ are often observed and play a central role in pathogenic remodeling and sudden cardiac death (SCD) (7). What is not well understood is the proximal biophysical cause by which mutation affects function at the molecular level.Due to both the size (ove...

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Section: Resultsmentioning

confidence: 99%

Atomic resolution probe for allostery in the regulatory thin filament

Williams

Lehman

Tardiff

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It is known that the tropomyosin gene has an important role in cellular architecture [Perry, 2001;Janco et al, 2013;Marston and Gautel, 2013;Gagat et al, 2016]. This gene has been mapped in the chromosomes of several Amazonian fish species, displaying a strong association with heterochromatic regions [Pinheiro et al, 2016].…”

Section: Discussionmentioning

confidence: 99%

Genomic Organization of Repetitive DNAs and Differentiation of an XX/XY Sex Chromosome System in the Amazonian Puffer Fish, <b><i>Colomesus asellus </i></b>(Tetraodontiformes)

Viana

Ezaz²,

Marajó

et al. 2017

Cytogenet Genome Res

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The genus Colomesus is the sole representative of the family Tetraodontidae in the Amazon region. Here, Colomesus asellus was analyzed using conventional and molecular cytogenetic protocols. Its diploid chromosome number is 2n = 46 with 12 meta-, 10 submeta-, 16 subtelo-, and 8 acrocentric chromosomes and a fundamental number of FN = 84. An XX/XY sex chromosome system was identified. Mapping of 18S rDNA correlated with the nucleolus organizer regions (Ag-NORs) in the short arms of the 2 X chromosomes in females and in the Y chromosome in males. C-banding revealed heterochromatin in the centromeric regions of all chromosomes, except for pair 3. Prominent sex chromosome-specific heterochromatin amplification was observed, covering the short arms of the Y chromosome almost entirely. FISH with telomeric and tropomyosin (tpm1) sequences, respectively, revealed terminal signals in all chromosomes. The analysis of extended DNA fibers confirmed the colocalization and the interspersed pattern of the telomeric and tpm1 sequences. Thus, this study highlights the remarkable evolutionary dynamism presented by the Amazonian puffer fish regarding the differentiation of a heteromorphic XY sex chromosome system and a particular sex-specific amplification of rDNA sites. This is the first record of such an association in the Tetraodontidae family.

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“…data]. Moreover, these genes are evolutionarily conserved and act in cellular activities such as cell migration, cell motility, cell transformation, cytokinesis, and muscle contraction [Vrhoviski et al, 2008;Chase et al, 2013;Janco et al, 2013].…”

Section: Discussionmentioning

confidence: 99%

“…The tropomyosin protein family is highly conserved within the vertebrates and is responsible for several cell functions, such as cell migration, cytokinesis, intracellular transportation, and muscle contraction [Vrhoviski et al, 2008;Barua, 2013]. The proteins are encoded by 4 distinct genes TPM1 (TPMα), TPM2 (TPMβ), TPM3 (TPMγ),and TPM4 (TPMδ) , and these genes present several isoforms produced by alternative splicing or alternative promoter processes [Vrhoviski et al, 2008;Barua, 2013;Janco et al, 2013].…”

mentioning

confidence: 99%

The Organization of Repetitive DNA in the Genomes of Amazonian Lizard Species in the Family Teiidae

Carvalho¹,

Pinheiro

Carmo³

et al. 2015

Cytogenet Genome Res

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Repetitive DNA is the largest fraction of the eukaryote genome and comprises tandem and dispersed sequences. It presents variations in relation to its composition, number of copies, distribution, dynamics, and genome organization, and participates in the evolutionary diversification of different vertebrate species. Repetitive sequences are usually located in the heterochromatin of centromeric and telomeric regions of chromosomes, contributing to chromosomal structures. Therefore, the aim of this study was to physically map repetitive DNA sequences (5S rDNA, telomeric sequences, tropomyosin gene 1, and retroelements Rex1 and SINE) of mitotic chromosomes of Amazonian species of teiids (Ameiva ameiva, Cnemidophorus sp. 1, Kentropyx calcarata, Kentropyx pelviceps, and Tupinambis teguixin) to understand their genome organization and karyotype evolution. The mapping of repetitive sequences revealed a distinct pattern in Cnemidophorus sp. 1, whereas the other species showed all sequences interspersed in the heterochromatic region. Physical mapping of the tropomyosin 1 gene was performed for the first time in lizards and showed that in addition to being functional, this gene has a structural function similar to the mapped repetitive elements as it is located preferentially in centromeric regions and termini of chromosomes.

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Polymorphism in tropomyosin structure and function

Cited by 30 publications

References 61 publications

Atomic resolution probe for allostery in the regulatory thin filament

Atomic resolution probe for allostery in the regulatory thin filament

Genomic Organization of Repetitive DNAs and Differentiation of an XX/XY Sex Chromosome System in the Amazonian Puffer Fish, <b><i>Colomesus asellus </i></b>(Tetraodontiformes)

The Organization of Repetitive DNA in the Genomes of Amazonian Lizard Species in the Family Teiidae

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