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TitleStructures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface.
Journal, issue, pagesNature, Vol. 600, Issue 7888, Page 339-343, Year 2021
Publish dateNov 10, 2021
AuthorsDevan Diwanji / Raphael Trenker / Tarjani M Thaker / Feng Wang / David A Agard / Kliment A Verba / Natalia Jura /
PubMed AbstractHuman epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact ...Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex 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 extracellulardomain 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.
External linksNature / PubMed:34759323 / PubMed Central
MethodsEM (single particle)
Resolution2.93 - 3.45 Å
Structure data

23916

7mn5

EMDB-23916: The HER2/HER3/NRG1b Heterodimer
PDB-7mn5: Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain
Method: EM (single particle) / Resolution: 2.93 Å

23917

7mn6

EMDB-23917: The HER2 S310F/HER3/NRG1b Heterodimer
PDB-7mn6: Structure of the HER2 S310F/HER3/NRG1b Heterodimer Extracellular Domain
Method: EM (single particle) / Resolution: 3.09 Å

23918

7mn8

EMDB-23918, PDB-7mn8:
Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain bound to Trastuzumab Fab
Method: EM (single particle) / Resolution: 3.45 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN / Complex / Receptor Tyrosine Kinase / SIGNALING PROTEIN/IMMUNE SYSTEM / Herceptin / Trastuzumab / SIGNALING PROTEIN-IMMUNE SYSTEM complex

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