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<p>Specific neurotrophic signaling by Trk receptors relies on the selective recruitment of downstream adaptors such as Dok5 and Dok6, yet the structural basis underlying this selectivity has remained unresolved. Here, we elucidate the principles governing Trk-Dok specificity by integrating structural prediction with biochemical validation. Comparative analysis of AlphaFold3-predicted complexes reveals that the intracellular domains of Trk dimers exhibit model-based interpretation, matching the distinct pocket architectures of Dok5 and Dok6. Ligand-induced phosphorylation exposes critical Trk tyrosine residues, enabling high-affinity engagement by adaptor PTB domains. We identify a conserved interaction hotspot centered on Trk Tyr515/516 and Dok Tyr187 that anchors this recognition. Crucially, co-immunoprecipitation assays validate that the C-terminal domains of Dok proteins exert modulatory control via steric hindrance, a finding consistent with our structural model. Collectively, our study establishes spatial complementarity and phosphorylation-dependent exposure of docking sites as key principles governing Trk-Dok signaling specificity, providing new structural insights into neurotrophin signaling and its potential therapeutic modulation.</p>

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Structural insights into the specificity of adaptor proteins Dok5 and Dok6 Docking to Trk receptors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Yingyao Wu,
  • Xiaojiao Sun,
  • Hongyue Chen,
  • Bin Yin,
  • Lin Hou,
  • Boqin Qiang,
  • Pengcheng Shu,
  • Xiaozhong Peng

摘要

Specific neurotrophic signaling by Trk receptors relies on the selective recruitment of downstream adaptors such as Dok5 and Dok6, yet the structural basis underlying this selectivity has remained unresolved. Here, we elucidate the principles governing Trk-Dok specificity by integrating structural prediction with biochemical validation. Comparative analysis of AlphaFold3-predicted complexes reveals that the intracellular domains of Trk dimers exhibit model-based interpretation, matching the distinct pocket architectures of Dok5 and Dok6. Ligand-induced phosphorylation exposes critical Trk tyrosine residues, enabling high-affinity engagement by adaptor PTB domains. We identify a conserved interaction hotspot centered on Trk Tyr515/516 and Dok Tyr187 that anchors this recognition. Crucially, co-immunoprecipitation assays validate that the C-terminal domains of Dok proteins exert modulatory control via steric hindrance, a finding consistent with our structural model. Collectively, our study establishes spatial complementarity and phosphorylation-dependent exposure of docking sites as key principles governing Trk-Dok signaling specificity, providing new structural insights into neurotrophin signaling and its potential therapeutic modulation.