Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface

Area of Science:

• Structural Biology
• Molecular Oncology
• Biochemistry

Background:

• The human epidermal growth factor receptor 2 (HER2) and HER3 receptors form a critical pro-oncogenic complex upon neuregulin-1β (NRG1β) binding.
• The precise mechanism of HER2-HER3 interaction and its structural basis have remained elusive due to a lack of structural data.

Purpose of the Study:

• To elucidate the structural mechanism of HER2-HER3 heterodimerization upon NRG1β binding.
• To investigate the impact of oncogenic mutations and therapeutic antibodies on the HER2-HER3 complex structure and dynamics.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structure of the near full-length NRG1β-bound HER2-HER3 dimer.
• Structural analysis of an oncogenic mutant HER2(S310F) and its interaction with HER3, NRG1β, and therapeutic antibodies (trastuzumab, pertuzumab).

Main Results:

• The study revealed unexpected dynamics at the HER2-HER3 dimerization interface, with the HER3 dimerization arm being unresolved in the presence of apo HER2.
• A compensatory interaction was observed in the HER2(S310F) mutant, stabilizing the dimer interface.
• While both HER2-HER3 and HER2(S310F)-HER3 bind trastuzumab, the mutant complex loses affinity for pertuzumab, indicating differential drug binding mechanisms.

Conclusions:

• The findings highlight the intrinsic dynamics of the HER2-HER3 heterodimer and how ligand occupancy is allosterically sensed at the dimerization interface.
• Therapeutic agents, like trastuzumab, exploit these receptor dynamics, similar to how oncogenic mutations do.
• The structural insights provide a basis for understanding HER2-HER3 complex formation and its modulation by mutations and targeted therapies.