Structural basis for signaling by the HER3 pseudokinase receptor

Abstract

The Human Epidermal Growth Factor Receptor 3 (HER3) is a pseudokinase receptor which contains a catalytically inactive kinase domain in its intracellular region. Despite lack of catalytic activity, HER3 is an essential signaling receptor serving as an allosteric activator of other HER receptors (EGFR and HER2), and a potent scaffold for recruitment an activation of PI3K. To form an active complex, HER3 and the orphan receptor HER2 assemble into a singly liganded, pro‐oncogenic heterocomplex upon binding to the HER3 ligand neuregulin‐1b (NRG1b). In the absence of structures of the HER2/HER3 heterodimer, the mechanism by which HER2 and HER3 interact upon ligand binding remains unknown. We isolated the near full‐length HER2/HER3 heterocomplex with their growth factor neuregulin (NRG) and obtained a 2.9Å cryo‐EM reconstruction of the extracellular domain module. We discovered an unexpected dynamics at the HER2/HER3 dimerization interface, which is exploited by oncogenic mutations and known therapeutics targeting HER2 – such as trastuzumab. The unique features of the NRG‐bound HER2/HER3 heterodimer underscore an allosteric connection between the ligand‐binding pocket and the dimerization interface, and explain why extracellular domains of unliganded HER2 do not homo‐associate via canonical active dimer interfaces.