Cryo-EM analysis uncovers the structure of the active, oncogenic HER2–HER3 heterodimer complex.

  • Major Finding: Cryo-EM analysis uncovers the structure of the active, oncogenic HER2–HER3 heterodimer complex.

  • Concept: The dimerization interface allosterically senses ligand occupancy to shift complex conformation.

  • Impact: This study uncovers dynamics of the HER2–HER3 dimer with implications for HER2-targeted therapies.

Commonly overexpressed or mutated in breast cancer and other solid tumors, human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase which activates signaling cascades that promote proliferation and tumorigenesis. As HER2 has no known activating ligand, HER2 heterodimerizes with ligand-binding HER family members, and the preferential heterodimerization of HER2 with HER3 is thought to allosterically activate the HER2 kinase. Despite the fact that HER2-targeted therapies are the standard of care for HER2-positive breast cancer, the molecular interactions within the pro-oncogenic HER2–HER3 heterodimer are still unknown. To address this, Diwanji, Trenker, and colleagues used cryo-electron microscopy (cryo-EM) to reconstruct the structure of the HER2–HER3 ectodomain heterodimer bound to the growth factor neuregulin-1β (NRG1β), resulting in a 2.9-angstrom structure of the HER2–HER3–NRG1β complex in which the HER2 and HER3 extracellular domains formed a “heart-shaped” dimer. Use of nearly full-length HER2 and HER3 receptors was necessary for this reconstruction and points to an essential role for all receptor domains in stabilization of the active receptor complex. In the structure, the dimerization arm in domain II of HER3 was unresolved, suggesting this region was not required for HER2 interaction. Comparison of the HER2–HER3–NRG1β structure with those of EGFR homodimers bound to the ligands epiregulin (EREG) or epidermal growth factor (EGF) supported an allosteric mechanism in which the mode of ligand binding, either fully or partially wedged, correlated with the conformation of the dimerization arm-binding pocket, ranging from closed, with high affinity for the dimerization arm, to open, with no dimerization arm binding. Upon formation of the HER2–HER3–NRG1β complex using mutant HER2 harboring S310F, the most frequent oncogenic missense mutation in HER2, S310F HER2 stabilized the HER3 dimerization arm and increased the total buried surface area between the HER2–HER3 interface. Additionally, visualization of a complex between the clinically approved HER2-targeting monoclonal antibody trastuzumab and HER2–HER3–NRG1β indicated subtle rearranging of the receptor to accommodate trastuzumab. In summary, this work uncovers the molecular structure of the dynamic heterodimer interface within the active, pro-oncogenic HER2–HER3 complex.

Diwanji D, Trenker R, Thaker TM, Wang F, Agard DA, Verba KA, et al. Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface. Nature 2021;600:339–43.

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