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

Devan Diwanji, Raphael Trenker, Tarjani M. Thaker, Feng Wang, David A. Agard, Kliment A. Verba () and Natalia Jura ()
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Devan Diwanji: University of California San Francisco
Raphael Trenker: University of California San Francisco
Tarjani M. Thaker: University of California San Francisco
Feng Wang: University of California San Francisco
David A. Agard: University of California San Francisco
Kliment A. Verba: University of California San Francisco
Natalia Jura: University of California San Francisco

Nature, 2021, vol. 600, issue 7888, 339-343

Abstract: Abstract Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex1–3 upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2–HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellular domain module, revealing unexpected dynamics at the HER2–HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2–HER3 and HER2(S310F)–HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)–HER3–NRG1β–trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2–HER3 heterodimer. The unique features of a singly liganded HER2–HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface.

Date: 2021
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DOI: 10.1038/s41586-021-04084-z

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