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<p>Cell adhesion molecules (CAMs) are pivotal in establishing and maintaining synaptic connectivity. Emerging evidence indicates that some secreted factors within the synaptic cleft, including C1q-like proteins (C1qls), play a crucial role in bridging pre- and post-synapses by connecting the bilateral CAMs. However, the mechanisms of those secreted factors in synapse assembly remain incomplete. Here, we explore C1ql-mediated synaptic connectivity, focusing on the assembly of C1ql1 and its postsynaptic receptor brain-specific angiogenesis inhibitor 3 (BAI3, also called ADGRB3). Our biochemical, structural, and computational analyses reveal that the trimeric globular C1q (gC1q) domain of C1ql1 undergoes a calcium-modulated domain-swapping event to form a hexamer. Cryo-EM study manifests the stabilizing role of calcium ions on the C1ql1_gC1q hexamer in complex with the extended CUB domain of BAI3. Using the gC1q hexamer, full-length C1ql1 further assembles into linear clusters, possibly providing a scaffold to accumulate BAI3 receptors on the plasma membrane. Our cellular and in vivo studies support a role for the gC1q-mediated dynamic assembly of C1ql1 in receptor accumulation and synapse maintenance. Collectively, our findings provide a plausible mechanism of secreted factor-mediated synaptic connectivity, driven by the calcium-modulated assembly of C1qls and their interactions with CAMs.</p>

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Structural basis of calcium-dependent C1ql1/BAI3 assemblies in synaptic connectivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Liangyu Liao,
  • Ying Han,
  • Fengfeng Niu,
  • Yingjie Wang,
  • Yang Lu,
  • Shun Xu,
  • Houming Zhu,
  • Leishu Lin,
  • Jinman Xiao,
  • Hoi In Tou,
  • Jiali Gao,
  • Bo Zhang,
  • Zhiyi Wei

摘要

Cell adhesion molecules (CAMs) are pivotal in establishing and maintaining synaptic connectivity. Emerging evidence indicates that some secreted factors within the synaptic cleft, including C1q-like proteins (C1qls), play a crucial role in bridging pre- and post-synapses by connecting the bilateral CAMs. However, the mechanisms of those secreted factors in synapse assembly remain incomplete. Here, we explore C1ql-mediated synaptic connectivity, focusing on the assembly of C1ql1 and its postsynaptic receptor brain-specific angiogenesis inhibitor 3 (BAI3, also called ADGRB3). Our biochemical, structural, and computational analyses reveal that the trimeric globular C1q (gC1q) domain of C1ql1 undergoes a calcium-modulated domain-swapping event to form a hexamer. Cryo-EM study manifests the stabilizing role of calcium ions on the C1ql1_gC1q hexamer in complex with the extended CUB domain of BAI3. Using the gC1q hexamer, full-length C1ql1 further assembles into linear clusters, possibly providing a scaffold to accumulate BAI3 receptors on the plasma membrane. Our cellular and in vivo studies support a role for the gC1q-mediated dynamic assembly of C1ql1 in receptor accumulation and synapse maintenance. Collectively, our findings provide a plausible mechanism of secreted factor-mediated synaptic connectivity, driven by the calcium-modulated assembly of C1qls and their interactions with CAMs.