ABB  Vol.3 No.1 , February 2012
Disorder structural predictions of the native EWS and its oncogenic fusion proteins in rapport with the function
ABSTRACT
The Intrinsic structural disorder (ISD) of native EWS and its fusion oncogenic proteins, including EWS/FliI, EWS/ATF1 and EWS/ZSG, was estimated by different Predictors. The ISD difference between the wild type and the oncogenic fusions found in the CTD is due to the fusion partner, usually a transcription factor (TF). A disordered region was found in the sequence (AA 132 - 156) of the NTD (EAD) of EWS, consisting of the longest region free of Y motifs. The IQ domain (AA 258 - 280), a Y-free region, flanked by two Y-boxes, is also disordered by all used Predictors. The EWS functional regions RGG1, RGG2 and RGG3 are predominantly disordered. A strong dependence was found between the structure of EWS protein and its oncogenic fusions, and their estimated ISD. The oncogenic function of the fusions is related to a decreased ISD in the CTD, due to the fused TF. The Predictors shown that the different isoforms have similar profiles, shifted with some amino acids, due to the translocations. On the bases of the prediction results, an analysis was made of the EWS sequence and its functional regions with increased ISD to make a relationship sequence-disorder-function that could be helpful in the design of antitumor agents against the corresponding malignances.

Cite this paper
Todorova, R. (2012) Disorder structural predictions of the native EWS and its oncogenic fusion proteins in rapport with the function. Advances in Bioscience and Biotechnology, 3, 25-34. doi: 10.4236/abb.2012.31005.
References
[1]   Spahn, L., Siligan, C., Bachmaier, R., Schmid, J.A., Aryee, D.A.T. and Kovar, H. (2003) Homotypic and heterotypic interactions of EWS, Fli-1 and their oncogenic fusion proteins. Oncogene, 22, 6819-6829. doi:10.1038/sj.onc.1206810

[2]   Ng, K.P., Potikyan, G., Savene, R.O.V., Denny, C.T., Uversky, V.N. and Lee, K.A.W. (2007) Multiple aromatic side chains within a disordere structure are critical for transcription and transforming activity of EWS family oncoproteins. PNAS, 104, 479-484. doi:10.1073/pnas.0607007104

[3]   Dosztanyi, Z., Csizmok, V., Tompa, P. and Simon, I. (2005) IUPred: Web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics, 21, 3433-3434. doi:10.1093/bioinformatics/bti541

[4]   Linding, R., Russell, R.B., Neduva, V. and Gibson, T.J. (2003) GlobPlot: Exploring protein sequences for globularity and disorder. Nucleic Acids Research, 31, 3701- 3708. doi:10.1093/nar/gkg519

[5]   Linding, R., Jensen, L.J., Diella, F., Bork, P., Gibson, T.J. and Russell, R.B. (2003) Protein disorder prediction: Implications for structural proteomics. Structure, 11, 1453- 1459. doi:10.1016/j.str.2003.10.002

[6]   Prilusky, J., Felder, C.E., Zeev-Ben-Mordehai, T., Rydberg, E.H., Man, O., Beckmann, J.S., Silman, I., Sussman, J.L. (2005) FoldIndex: A simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics, 21, 3435-3438. doi:10.1093/bioinformatics/bti537

[7]   Yang, Z.R., Thomson, R., McNeil, P. and Esnouf, R.M. (2005) RONN: The bio-basis function neural network technique applied to the detection of natively disordered regions in proteins. Bioinformatics, 21, 3369-3376. doi:10.1093/bioinformatics/bti534

[8]   Xue, B., Dunbrack, R.L., Williams, R.W., Dunker, A.K. and Uversky, V.N. (2010) PONDR-FIT: A meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta, 1804, 996-1010.

[9]   Obradovic, Z., Peng, K., Vucetic, S., Radivojac, P., Brown, C.J. and Dunker, A.K. (2003) Predicting intrinsic disorder from amino acid sequence. Proteins, 53, 566-572. doi:10.1002/prot.10532

[10]   Uversky, V.N., Oldfield, C.J., Midic, U., Xie, H., Xue, B., Vucetic, S., Iakoucheva, L.M., Obradovic, Z. and Dunker, A.K. (2009) Unfoldomics of human diseases: Linking protein intrinsic disorder with diseases. BMC Genomics, 10, S7. doi:10.1186/1471-2164-10-S1-S7

[11]   Liu, J., Perumal, N.B., Oldfield, C.J., Su, E.W., Uversky, V.N. and Dunker, A.K. (2006) Intrinsic disorder in transcription factors. Biochemistry, 45, 6873-6888. doi:10.1021/bi0602718

[12]   Hegyi, H., Buday, L. and Tompa, P. (2009) Intrinsic Structural Disorder Confers Cellular Viability on Oncogenic Fusion Proteins. PLoS Computational Biology, 5, e1000552. doi:10.1021/bi0602718

[13]   Pan, S., Ming, K.Y., Dunn, T.A., Li, K.K. and Lee, K.A. (1998) The EWS/ATF1 fusion protein contains a dispersed activation domain that functions directly. Oncogene, 16, 1625-1631. doi:10.1038/sj.onc.1201671

[14]   Heyerdahl, S.L., Rozenberg, J., Jamtgaard, L., Rishi, V., Varticovski, L., Akah, K., Scudiero, D., Shoemaker, R.H., Karpova, T.S., Day, R.N., McNally, J.G. and Vinson, C. (2010) The arylstibonic acid compound NSC13746 disrupts B-ZIP binding to DNA in living cells. European Journal of Cell Biology, 89, 564-573. doi:10.1016/j.ejcb.2009.11.029

[15]   Bertolotti, A., Melot, T., Acker, J., Vigneron, M., Dellatre, O. and Tora, L. (1998) EWS, but not EWS-Fli-1, is associated with both TFIID and RNA-polymerase II: Interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA Polymerase II complexes. Molecular Cell Biology, 18, 1489-1497.

[16]   Uren, A., Tcherkasskaya, O. and Toretsky, J.A. (2004) Recombinant EWS-FLI1 oncoprotein activates transcription. Biochemistry, 42, 13579-13589. doi:10.1021/bi048776q

[17]   Kim, J., Lee, J.M., Branton, P.E. and Pelletier, J. (1999) Modification of EWS/WT1 functional properties by phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 96, 14300- 14305. doi.org/10.1073/pnas.96.25.14300

[18]   Butticè, G., Duterque-Coquillaud, M., Basuyaux, J.P., Carrère, S., Kurkinen, M. and Stéhelin, D. (1996) Erg, an Ets-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. Oncogene, 13, 2297-2306.

[19]   Basuyaux, J.P., Ferreira, E., Stéhelin, D. and Butticè, G. (1997) The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner. Journal of Biological Chemistry, 272, 26188- 26195. doi.org/10.1074/jbc.272.42.26188

[20]   Lee, K.A. (2007) Ewings family oncoproteins: drunk, disorderly and in search of partners. Cell Research, 17, 286-288. doi:10.1038/cr.2007.22

[21]   Taggart, A.K. and Pugh, B.F. (1996) Dimerization of TFIID when not bound to DNA. Science, 272, 1331-1333. doi:10.1126/science.272.5266.1331

[22]   Carrère, S., Verger, A., Flourens, A., Stehelin, D. and Duterque-Coquillaud, M. (1998) Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains. Oncogene, 16, 3261-3268. doi:10.1038/sj.onc.1201868

[23]   Todorova, R. (2009) In vitro interaction between the N-terminus of the Ewing’s sarcoma protein and the subunit of RNA polymerase II hsRPB7. Molecular Biology Reports, 36, 1269-1274. doi:10.1007/s11033-008-9308-2

[24]   Erkizan, H.V., Kong, Y., Merchant, M., Schlottmann, S., Barber-Rotenberg, J.S., Yuan, L., Abaan, O.D., Chou, T.-H., Dakshanamurthy, S., Brown, M.L., Uren, A. and Toretsky, J.A. (2009) A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing’s sarcoma. Nature Medicine, 15, 750-757. doi:10.1038/nm.1983

 
 
Top