Structural basis for constitutive activation of oncogenic gp130 mutants in human inflammatory hepatocellular adenomas

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors primarily driven by somatic mutations in the gp130 receptor, resulting in its constitutive activation. To uncover the structural mechanisms underlying this activation, we employed cryo-electron microscopy and mutagenesis to study five representative IHCAs-associated gp130 mutants and two engineered mutants with ligand-independent activity. Most mutants formed “X”-shaped dimers through a 3D domain-swapping mechanism, characterized by large juxtamembrane separations and reliant on D1 domain-mediated “tip-to-tip” interactions for dimer clustering and activation. A rare mutant displayed a distinct “Y”-shaped dimer conformation, with closely aligned juxtamembrane domains enabling direct activation independent of dimer clustering. These findings highlight the diversity of gp130 mutant activation mechanisms and provide a foundation for developing therapeutic strategies targeting aberrant gp130 signaling in IHCAs.