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Disordered binding regions of Ewing’s sarcoma fusion proteins

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 ESFTs because of high patient mortality in cases of metastatic disease.

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Abbreviations

EWS:

Ewing’s sarcoma protein

CTD, NTD:

C- and N-terminal domain

ID:

intrinsic disorder

ISD:

intrinsic structural disorder

IPD:

intrinsic protein disorder

IDPs:

intrinsically disordered proteins

DBRs:

disordered binding regions

EAD:

EWS activation domain

AA:

amino acid

TAD:

transcription activation domain

PBR:

protein binding regions

Pol II:

RNA polymerase II

TF:

transcription factor

ESFT:

Ewing’s sarcoma family of tumors

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Correspondence to R. Todorova.

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Todorova, R. Disordered binding regions of Ewing’s sarcoma fusion proteins. Russ J Bioorg Chem 40, 16–25 (2014). https://doi.org/10.1134/S1068162014010117

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  • DOI: https://doi.org/10.1134/S1068162014010117

Keywords

  • Ewing’s sarcoma protein
  • EWS oncogenic fusions
  • function-structure-disorder
  • predictors
  • targeted inhibition
  • intrinsically disordered proteins
  • disordered binding regions