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.
Highlights
INTRODUCTIONEwing’s Sarcoma Oncogene (EWS) on chromosome 22q12 is encoding a RNA binding protein that is target of tumor-specific chromosomal translocations in Ewing sarcoma tumor, Myxoid liposarcoma, Malignant melanoma of soft parts, Desmoplastic small round cell tumor,
Ewing’s Sarcoma Oncogene (EWS) on chromosome 22q12 is encoding a RNA binding protein that is target of tumor-specific chromosomal translocations in Ewing sarcoma tumor, Myxoid liposarcoma, Malignant melanoma of soft parts, Desmoplastic small round cell tumor, Peripheral neurectodermal tumour, Angiomatoid fibrous histiocytoma, Extra-skeletal myxoid chondrosarcomas, Rhabdomyosarcoma, Locally destructive tumour, Myoepithelioma tumours of soft tissue, Hidradenoma or eccrine acrospiroma, Mucoepidermoid carcinoma, Neuroblastoma, Olfactory neuroblastoma, Solid pseudopapillary tumour of the pancreas and Acute myeloid leukemia
On the bases of the prediction results, an analysis was made of the EWS sequence and its functional regions with increased Intrinsic structural disorder (ISD) to make a relationship sequence-disorder-function that could be helpful in the design of antitumor agents against the corresponding malignances
Summary
Ewing’s Sarcoma Oncogene (EWS) on chromosome 22q12 is encoding a RNA binding protein that is target of tumor-specific chromosomal translocations in Ewing sarcoma tumor, Myxoid liposarcoma, Malignant melanoma of soft parts, Desmoplastic small round cell tumor,. The interaction mechanism of EWS in self-association and oligomerization involves N-terminal and centrally localized amino acids, while for optimal association are required full-length EWS molecules [1]. The EWS activation domain (EAD) is located within its N-terminal 286 amino acids, and like many chromatin organizing proteins is an intrinsically disordered (ID) protein [2]. Is made an attempt to estimate the Intrinsic structural disorder (ISD) of EWS and its reported fusion oncogenic proteins by different methods of prediction. 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-disorderfunction that could be used to design antitumor agents against the corresponding malignances
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