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<p>The receptor tyrosine kinase ROS1 plays essential roles in cell growth and sperm maturation, yet its activation mechanism has remained poorly understood. Here, we report high-resolution cryo-electron microscopy (cryo-EM) structures of chicken ROS1 in its ligand-free form, in complex with its ligand NEL, and with the ligand/co-ligand complex NEL/NICOL. Unliganded ROS1 adopts an arc-shaped conformation. The interaction between NEL and ROS1 is mediated by the VWC2 domain of NEL and the β1 domain of ROS1. Binding of NICOL to the coiled-coil domain of NEL stabilizes NEL into a batwing-shaped asymmetric dimer, which can recruit only one ROS1 molecule due to steric hindrance. Structural analyses and biochemical results suggest that the 2:1 NEL/NICOL complexes further oligomerize through LamG–VWC4 domain interactions, facilitating the clustering of multiple ROS1 for its activation. Functional assays confirm that both NICOL and the multimerization of NEL/NICOL complexes are required for robust ROS1 signaling. Our findings establish NICOL as a critical co-ligand for ROS1 and suggest a distinct ligand-driven oligomerization mechanism for ROS1 activation.</p>

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Structural insights into the activation of the chicken ROS1 receptor by the NEL/NICOL ligand complex

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Weidong An,
  • Xuewu Zhang,
  • Xiao-chen Bai

摘要

The receptor tyrosine kinase ROS1 plays essential roles in cell growth and sperm maturation, yet its activation mechanism has remained poorly understood. Here, we report high-resolution cryo-electron microscopy (cryo-EM) structures of chicken ROS1 in its ligand-free form, in complex with its ligand NEL, and with the ligand/co-ligand complex NEL/NICOL. Unliganded ROS1 adopts an arc-shaped conformation. The interaction between NEL and ROS1 is mediated by the VWC2 domain of NEL and the β1 domain of ROS1. Binding of NICOL to the coiled-coil domain of NEL stabilizes NEL into a batwing-shaped asymmetric dimer, which can recruit only one ROS1 molecule due to steric hindrance. Structural analyses and biochemical results suggest that the 2:1 NEL/NICOL complexes further oligomerize through LamG–VWC4 domain interactions, facilitating the clustering of multiple ROS1 for its activation. Functional assays confirm that both NICOL and the multimerization of NEL/NICOL complexes are required for robust ROS1 signaling. Our findings establish NICOL as a critical co-ligand for ROS1 and suggest a distinct ligand-driven oligomerization mechanism for ROS1 activation.