Scholarlink

<p>Epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of many human cancers. In addition to the extracellular ligand-binding domain and intracellular kinase domain of EGFR that have been widely investigated over the past decades, the function and role of the carboxy-terminal tail (C-tail) still remains largely unexplored to date. In this study, the intramolecular interaction of EGFR kinase domain with C-tail was characterized systematically at structural, energetic and dynamic levels; a 13-mer hotspot segment (<sup>1007</sup>MDDVVDADEYLIP<sup>1019</sup>) was identified as self-binding peptide (SBP) in the first ~ 80-residue region of C-tail that plays an important role in the interaction, in which the Tyr1016 residue serves as a trigger to regulate the binding state of SBP, that is, the SBP can bind to/unbind from the kinase domain upon pTyr1016 dephosphorylation/Tyr1016 phosphorylation, thus working as a molecular switch to control the auto-inhibitory state of the C-tail. The SBP-derived peptide is intrinsically disordered and thus only exhibits a moderate affinity to EGFR kinase domain, which can be constrained into an ordered one-turn helical conformation by designing a disulfide cyclization across its residue foothold[1012,1015]. The designed cyclic peptide is an effective self-competitor with the native SBP segment for their cognate docking site, which can competitively disrupt the native intramolecular interaction between EGFR kinase domain and C-tail with a high potency. It is suggested that the SBP molecular switch is responsible for the dynamic regulation of domain–tail interactions triggered by Tyr1016 phosphorylation state, which may further influence the EGFR dimerization, activation and signaling.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Structure-based identification, phosphorylation, cyclization and engineering of a self-binding peptide carboxy-terminal to EGFR kinase domain by integrating dynamics simulation, energetics calculation and fluorescence analysis

  • 期刊论文

  • 发表日期：

    2026年2月20日

查看全文
  • Jingjing Chen,
  • Tianyu Wang,
  • Lijuan Shi

摘要

Epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of many human cancers. In addition to the extracellular ligand-binding domain and intracellular kinase domain of EGFR that have been widely investigated over the past decades, the function and role of the carboxy-terminal tail (C-tail) still remains largely unexplored to date. In this study, the intramolecular interaction of EGFR kinase domain with C-tail was characterized systematically at structural, energetic and dynamic levels; a 13-mer hotspot segment (1007MDDVVDADEYLIP1019) was identified as self-binding peptide (SBP) in the first ~ 80-residue region of C-tail that plays an important role in the interaction, in which the Tyr1016 residue serves as a trigger to regulate the binding state of SBP, that is, the SBP can bind to/unbind from the kinase domain upon pTyr1016 dephosphorylation/Tyr1016 phosphorylation, thus working as a molecular switch to control the auto-inhibitory state of the C-tail. The SBP-derived peptide is intrinsically disordered and thus only exhibits a moderate affinity to EGFR kinase domain, which can be constrained into an ordered one-turn helical conformation by designing a disulfide cyclization across its residue foothold[1012,1015]. The designed cyclic peptide is an effective self-competitor with the native SBP segment for their cognate docking site, which can competitively disrupt the native intramolecular interaction between EGFR kinase domain and C-tail with a high potency. It is suggested that the SBP molecular switch is responsible for the dynamic regulation of domain–tail interactions triggered by Tyr1016 phosphorylation state, which may further influence the EGFR dimerization, activation and signaling.