Targeting rho guanine nucleotide exchange factor ARHGEF5/TIM with auto-inhibitory peptides in human breast cancer

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• 作者：Ou Huang ; Dandan Wu ; Feiyan Xie ; Lili Lin ; Xiaobo Wang ; Min Jiang ; Yafen Li…
• 关键词：ARHGEF5/TIM ; DH domain ; Auto ; inhibitory helix ; Peptide ; Breast cancer
• 刊名：Amino Acids
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：47
• 期：6
• 页码：1239-1246
• 全文大小：3,061 KB
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• 作者单位：Ou Huang (1)
  Dandan Wu (2)
  Feiyan Xie (3)
  Lili Lin (3)
  Xiaobo Wang (3)
  Min Jiang (4)
  Yafen Li (1)
  Weiguo Chen (1)
  Kunwei Shen (1)
  Xiaoqu Hu (3)
  
  1. Department of Surgery, Ruijin Hospital, Medical School of Shanghai Jiaotong University, Shanghai, 200025, China
  2. International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai, 200023, China
  3. Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
  4. Department of Breast Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Analytical Chemistry
  Biochemical Engineering
  Life Sciences
  Proteomics
  Neurobiology
  
• 出版者：Springer Wien
• ISSN：1438-2199

文摘

The oncogenic protein ARHGEF5/TIM has long been known to express specifically in human breast cancer and other tumors, which is an important member of Rho guanine nucleotide exchange factors that activate Rho-family GTPases by promoting GTP/GDP exchange. The activation capability of TIM is auto-inhibited by a putative helix N-terminal to Dbl homology (DH) domain, which is stabilized by intramolecular interaction of Src homology 3 domain with a poly-proline sequence that locates between the helix and DH domain. Here, we attempted to target TIM DH domain using the modified versions of its auto-inhibitory helix. In the procedure, bioinformatics techniques were used to investigate the intramolecular interaction of DH domain with auto-inhibitory helix and, based on obtained knowledge, to optimize physicochemical property and structural conformation for the helix. We also performed affinity assay to determine the binding strength of modified peptides to DH domain. Consequently, two modified peptides, namely, DALYEEYNLVV and EVLYEEYQLVV were found as good binders of DH domain with dissociation constants K _d of 0.35 and 2?μM, respectively. Structural analysis revealed that the charge neutralization and electrostatic interaction confer additional stability for these two peptide complexes with DH domain.