Current Science

Open Access Open Access  Restricted Access Subscription Access

Computational Modelling of Human Sarcomeric Telethonin Protein and Predicting the Functional effect of Missense Single Nucleotide Polymorphsim


Affiliations
1 Department of Zoology, University of Calicut, Malappuram 673 635, India
 

Telethonin (T-cap) is a 19 kDa protein and in humans it is encoded by the TCAP gene chr17q12. Telethonin is expressed in cardiac and skeletal muscle at Z-discs. Telethonin binds to the titin Z1–Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Variation in Telethonin implicates several diseases, including limb-girdle muscular dystrophy, cardiomyopathy, dilated and idiopathic cardiomyopathy. This protein variation study helps us understand the several cardiac and muscular disorders related to missense single nucleotide polymorphisms (SNPs) mutation and specified drug designing. Here we evaluate computational analysis of missense SNPs present in the TCAP gene. It was performed by considering 13 prediction tools in order to select the deleterious variations and followed by molecular modelling, evolutionary conservation analysis, signal peptide prediction and model validation. It has been found that eight deleterious variants, out of which three (Arg70Trp, Pro90Leu and Arg106Cys) are previously associated with human diseases.

Keywords

Computational Analysis, Genetic Diseases, Human Sarcomeric Protein, Missense Single Nucleotide Polymorphism.
User
Notifications
Font Size

  • Miller, M. P. and Kumar, S., Understanding human disease mutation through the use of interspecific genetic variation. Hum. Mol. Genet., 2001, 10, 2319, 2328.

  • Fulkner, G., Lanfranchi, G. and Valle, G., Telethonin and other new proteins of the Z disc of skeletal muscle. IUBMB Life, 2001, 51, 275–282.

  • Kojic, S. et al., The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle. J. Mol. Biol., 2004, 339, 313– 325.

  • Faulkner, G. et al., FATZ. A Filamin, actinin and telethonin binding protein of the Z-disc of skeletal muscle. J. Biol. Chem., 2000, 275, 41234–41242.

  • Frey, N. and Olson, E. N., Calsarcin-3, a novel skeletal muscle specific member of the calsarcin family, interacts with multiple Z-disc proteins. J. Biol. Chem., 2002, 277, 13998–14004.

  • Kleywegt, G. J. and Jones, T. A., Phi/Psi-chology: Ramachandran revisited. Structure, 1996, 4, 1395–1400.

  • Furukawa, T. et al., Specific interaction of the potassium channel beta-subunit mink with the sarcomeric protein T-cap suggests a T-tubule myofibril linking system. J. Mol. Biol., 2001, 313, 775– 784.

  • Mayans, O. et al., Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature, 1998, 395, 863– 869.

  • Moreira, E. S. et al., Limb girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nature Genet., 2000, 24, 163–166.

  • Hayashi, T., Arimura, T. and Itochsatoh, M., T-cap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J. Am. Coll. Cardiol., 2004, 44, 2192–2201.

  • Knoll, R. et al., The cardiac mechanical stretch sensor machinery involves A Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell, 2002, 111, 943–955.

  • Kumar, P., Henikoff, S. and Ng, P. C., Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature Protoc., 2009, 4, 1073–1081.

  • Choi, Y. et al., Predicting the functional effect of amino acid substitutions and indels. PLOS ONE, 2012, 7, e46688; doi:10.1371/ journal.pone.0046688.

  • Mi, H. et al., The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids, 2005, 33.

  • Bromberg, Y., Yachdav, G. and Rost, B., SNAP predicts effect of mutations on protein function. Bioinformatics, 2008, 24, 2397– 2398.

  • Pires, A. S. et al., In Silico analyses of deleterious missense SNPs of human apolipoprotein E3. Nature Sci. Rep., 2017, 7, 2509.

  • Adzhubei, I. A. et al., A method and server for predicting damaging missense mutations. Nature Methods, 2010, 7, 248–249.

  • Capriotti, E., Calabrese, R. and Casadio, R., Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics, 2006, 22, 2729–2734.

  • Bendl, J. et al., Predict SNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLOS Comput. Biol., 2014, 10, e1003440.

  • Niroula, A., Urolagin, S. and Vihinen, M., PON-P2: prediction method for fast and reliable identification of harmful variants. PLOS ONE, 2015, 10(2), e0117380.

  • Askenazy, H. et al., ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res., 2010, 38, W529–W533; doi:10.1093/ nar/gkq399.

  • Haworth, R. S. et al., Protein kinase D is a novel mediator of cardiac troponin 1 phosphorylation and regulates myofilament function. Circ. Res., 2004, 95, 1091–1099.

  • Sitao, W. and Zhang, Y., MUSTER: improving protein sequence profile–profile alignments by using multiple sources of structure information. Proteins, 2008, 72(2), 547–556.

  • Laskowaski, R. A. et al., PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr., 1993, 26, 283–291.

  • Laskowaski, R. A., Chistyakov, V. V. and Thornton, J. M., PDBsum more: new summaries and analyses of the known 3D structures of proteins and nucleic acids. Nucleic Acids Res., 2005, 33, 266–268.

  • Lindahl, E. et al., NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all atom normal mode analysis. Nucleic Acids Res., 2006, 34, 52–60.

  • Gopalakrishnan, K. et al., Ramachandran plot on the web (2.0). Protein Pept. Lett., 2007, 14, 669–671.

  • Angermuller, C. et al., Discriminating modelling of contextspecific amino acid substitution probabilities. Bioinformatics, 2012, 28, 3240–3247.

  • Celniker, G. et al., ConSurf: using evolutionary data to raise testable hypothesis about protein function. Isr. J. Chem., 2013, 53, 199–206.

  • Sherry, S. T. et al., dbSNP: the NCBI database of genetic variation. Nucleic Acids Res., 2001, 29, 308–311.

  • Porto, W. F., Franco, O. L. and Alencar, S. A., Computational analysis and prediction of guanylin deleterious SNPs. Peptides, 2015, 69, 92–102.

  • Mazzone, A. et al., A mutation in Telethonin alters Nav1.5 function.J. Biol. Chem., 2008, 283, 16537–16544.

  • Francis, A. et al., Novel TCAP mutation C.32C >A causing limb girdle muscular dystrophy 2G. PLOS ONE, 2014, 9(7), e102764.

  • Mues, A. et al., Two immunoglobulin like domains of the Z-disc portion of titin interact in a conformation dependent way with telethonin. FEBS Lett., 1998, 428, 111–114.

  • Arnold, K. et al., The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics, 2006, 22, 195–201.

  • Gopalakrishnan, C. et al., Computational modelling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer. Nature Sci. Rep., 2017, 7, 43830.

  • Valle, G. et al., Telethonin, a novel sarcomeric protein of heart and skeletal muscle. FEBS Lett., 1997, 415, 163–168.

  • Li, W. and Godzik, A., Cd hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics, 2006, 22, 1658–1659.

  • Nicholas, G. et al., Titin-cap associates with and regulates secretion of myostatin. J. Cell Physiol., 2002, 193, 120–131.

  • Nikos, P. et al., Evidence for a dimeric assembly of titin/ telethonin complexes induced by the telethonin C-terminus. J. Struct.. Biol., 2006, 155, 239–250.

  • Suzek, B. E. et al., Uniref: comprehensive and non-redundant UniProt reference clusters. Bioinformatics, 2007, 23, 1282–1288.

  • Dakal, T. C., Kala, D. and Dhiman, G., Predicting the functional consequences of non-synonymous single nucleotide polymorphism in IL8 gene. Nature. Sci. Rep., 2017, 7(1), 6525.

  • Van Oeveren, J. and Janssen, A., A single nucleotide polymorphisms. Single Nucleotide Polymorph., 2009, 578, 73–91.

  • Yue, P. and Moult, J., Identification and analysis of deleterious human SNPs. J. Mol. Biol., 2006, 356, 1263–1274.


Abstract Views: 237

PDF Views: 82




  • Computational Modelling of Human Sarcomeric Telethonin Protein and Predicting the Functional effect of Missense Single Nucleotide Polymorphsim

Abstract Views: 237  |  PDF Views: 82

Authors

P. P. Anand
Department of Zoology, University of Calicut, Malappuram 673 635, India

Abstract


Telethonin (T-cap) is a 19 kDa protein and in humans it is encoded by the TCAP gene chr17q12. Telethonin is expressed in cardiac and skeletal muscle at Z-discs. Telethonin binds to the titin Z1–Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Variation in Telethonin implicates several diseases, including limb-girdle muscular dystrophy, cardiomyopathy, dilated and idiopathic cardiomyopathy. This protein variation study helps us understand the several cardiac and muscular disorders related to missense single nucleotide polymorphisms (SNPs) mutation and specified drug designing. Here we evaluate computational analysis of missense SNPs present in the TCAP gene. It was performed by considering 13 prediction tools in order to select the deleterious variations and followed by molecular modelling, evolutionary conservation analysis, signal peptide prediction and model validation. It has been found that eight deleterious variants, out of which three (Arg70Trp, Pro90Leu and Arg106Cys) are previously associated with human diseases.

Keywords


Computational Analysis, Genetic Diseases, Human Sarcomeric Protein, Missense Single Nucleotide Polymorphism.

References





DOI: https://doi.org/10.18520/cs%2Fv117%2Fi4%2F638-648