Disordered binding regions of Ewing's sarcoma fusion proteins.

Bioorganicheskaia khimiia Pub Date : 2014-01-01
R Todorova
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Abstract

A relationship was found between the Amino acid (AA) composition, Intrinsic Protein Disorder (IPD) and Protein Binding Regions (PBRs) of the functional regions of Ewing's sarcoma protein (EWS) and oncogenic EWS fusion proteins (EFPs). EWS has high IPD and 64% predicted Disordered Binding Regions (DBRs) by ANCHOR. The native Transcription Factors, fused to EWS Activation Domain (EAD) in EFPs, show high DBRs in N-terminal domain and relatively low in C-terminal domain. EFPs oncogenic function is related to IPD and PBRs probabilities, high around breakpoint and decreased in the fused Transcription Factor. The increased IPD in EAD around (AA 82), and the small RBRs around (AAs (50-60) and 100) are consistent with the reported physical interactions with RNA Polymerase II subunits. The AAs (228-264) of EWS, interacting with ZFM1 (SF1), correspond to two peaks of DBRs by Anchor and high IPD by IUPred. The IQ domain of EAD (AAs 258-280) that is phosphorylated by PKC and interacts with calmodulin, has high IPD and DBRs probability. The Ser266, conserved site of PKC phosphorylation, is situated in DBR and IPD region with about 100% probability. The small PBRs found in the EAD correspond to important physical protein-protein interactions, confirmed by experimental data. Thus regions of EWS and EFPs, included in functional interactions with other partners, are enriched of Protein Binding Regions by ANCHOR. The development of IPD- and PBRs-related, EWS-FLI1-directed specific therapies will help the design of antitumor agents against ESFT because of high patient mortality in cases of meta- static disease.

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尤文氏肉瘤融合蛋白的无序结合区。
发现Ewing肉瘤蛋白(EWS)功能区域的氨基酸(AA)组成、内在蛋白紊乱(IPD)和蛋白结合区(PBRs)与致癌性EWS融合蛋白(EFPs)之间存在相关性。EWS的IPD高,锚定预测的DBRs为64%。在EFPs中融合到EWS激活域(EAD)的天然转录因子在n端域表现出较高的dbr,在c端域表现出相对较低的dbr。EFPs的致癌功能与IPD和PBRs概率有关,在断点附近高,在融合转录因子中降低。在EAD (AA 82)附近IPD增加,在AAs(50-60)和100附近rbr小,这与报道的RNA聚合酶II亚基的物理相互作用一致。EWS的AAs(228-264)与ZFM1 (SF1)相互作用,对应Anchor的两个dbr峰和iuppred的高IPD峰。EAD的IQ结构域(AAs 258-280)被PKC磷酸化并与钙调蛋白相互作用,具有较高的IPD和dbr概率。PKC磷酸化的保守位点Ser266位于DBR和IPD区,概率约为100%。实验数据证实,在EAD中发现的小pbr与重要的物理蛋白质-蛋白质相互作用相对应。因此,EWS和EFPs的区域,包括与其他伙伴的功能相互作用,被锚蛋白结合区富集。IPD和pbrs相关、ews - fli1导向的特异性疗法的发展将有助于设计针对ESFT的抗肿瘤药物,因为ESFT在meta- static病例中患者死亡率很高。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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