Cryo-EM structures of the near full-length HER2/HER3 heterodimer reveal a novel allosteric mechanism of activation

Abstract

The human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3) form a potent pro-oncogenic signaling unit upon binding to the extracellular ligand neuregulin-1ß (NRG1ß). Through single particle cryo-electron microscopy (cryo-EM) on graphene oxide (GO) supported grids, we have solved three novel structures of the HER2/HER3 heterodimer in the context of near-full length receptors. These structures represent the first depictions of a singly-liganded HER receptor dimer, of HER2 actively engaged with a co-receptor, and of HER3 in a ligand-bound configuration.