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The Antiangiogenic and Antitumor Activities of the N-Terminal Fragment of Endostatin Augmented by Ile/Arg Substitution: The Overall Structure Implicated the Biological Activity Publisher



Chamani R1 ; Asghari SM1 ; Alizadeh AM2 ; Mansouri K3 ; Doroudi T4 ; Kolivand PH4 ; Ghafouri H1 ; Ehtesham S5 ; Rabouti H1 ; Mehrnejad F6
Authors
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Authors Affiliations
  1. 1. Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
  2. 2. Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
  4. 4. Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
  5. 5. Department of Biology, Faculty of Science, Islamic Azad University, Parand, Iran
  6. 6. Department of Life Sciences Engineering, Faculty of New Sciences & Technologies, University of Tehran, Iran

Source: Biochimica et Biophysica Acta - Proteins and Proteomics Published:2016


Abstract

The antiangiogenic and antitumor activities of the 27-amino acid fragment corresponding to the N-terminal domain of endostatin were shown to be dependent on a Zn-binding loop in the N-terminus. To investigate whether the regions outside of the N-terminal loop play a role in the peptide function, the structure and function of a variant containing Ile26Arg mutation (ES-R) were compared with those of the native peptide (ES-Zn). Structural analysis using far-UV CD, intrinsic fluorescence and molecular dynamics simulation provided information regarding the overall changes upon the mutation. In addition, the docking simulations predicted a higher affinity of ES-R to integrins αvβ3 and α5β1 than ES-Zn and a profound reorganization of the binding residues throughout the sequence. In Human Umbilical Vein Endothelial Cells (HUVECs), ES-R inhibited the tube formation and activated caspase-3 more strongly than do ES-Zn. Based on in vivo studies, the growth of breast tumor and expression of CD31, Bcl-2 and nonfunctional p53 were inhibited more effectively by ES-R than by ES-Zn. We conclude that the C-terminal region is involved in the peptide function through some global structural effects. © 2016 Elsevier B.V.
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