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<p>Latrophilins are conserved adhesion-type G-protein-coupled receptors associated with embryonic defects and lethality. However, their mechanistic roles and ligands in embryogenesis remain unknown. Here, we identified TOL-1, the sole Toll-like receptor in <i>Caenorhabditis elegans</i>, as a ligand for the <i>C.</i> <i>elegans</i> latrophilin, LAT-1. The extracellular lectin domain of LAT-1 directly binds to the second leucine-rich repeat domain of TOL-1. The crystal structure and cryo-electron microscopy density map of the LAT-1–TOL-1 extracellular region complex reveal a one-to-one lectin domain interaction with the convex face of a leucine-rich repeat domain. In <i>C.</i> <i>elegans</i>, endogenous mRNA and protein localization analyses showed mutually exclusive sites of expression, suggesting that in vivo LAT-1–TOL-1 interactions mostly occur in <i>trans</i>. Mutagenesis of key interface residues that disrupt the LAT-1–TOL-1 interaction led to partial lethality and malformed embryos. Thus, TOL-1 binding to LAT-1 represents a receptor–ligand axis essential for animal development.</p>

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Structural basis and functional roles for Toll-like receptor binding to Latrophilin in C. elegans development

  • 期刊论文

  • 发表日期：

    2025年6月30日

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  • Gabriel Carmona-Rosas,
  • Jingxian Li,
  • Jayson J. Smith,
  • Wioletta I. Nawrocka,
  • Shouqiang Cheng,
  • Elana E. Baltrusaitis,
  • Minglei Zhao,
  • Demet Araç,
  • Paschalis Kratsios,
  • Engin Özkan

摘要

Latrophilins are conserved adhesion-type G-protein-coupled receptors associated with embryonic defects and lethality. However, their mechanistic roles and ligands in embryogenesis remain unknown. Here, we identified TOL-1, the sole Toll-like receptor in Caenorhabditis elegans, as a ligand for the C. elegans latrophilin, LAT-1. The extracellular lectin domain of LAT-1 directly binds to the second leucine-rich repeat domain of TOL-1. The crystal structure and cryo-electron microscopy density map of the LAT-1–TOL-1 extracellular region complex reveal a one-to-one lectin domain interaction with the convex face of a leucine-rich repeat domain. In C. elegans, endogenous mRNA and protein localization analyses showed mutually exclusive sites of expression, suggesting that in vivo LAT-1–TOL-1 interactions mostly occur in trans. Mutagenesis of key interface residues that disrupt the LAT-1–TOL-1 interaction led to partial lethality and malformed embryos. Thus, TOL-1 binding to LAT-1 represents a receptor–ligand axis essential for animal development.