7mn8 › Citations

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

Diwanji D, Trenker R, Thaker TM, Wang F, Agard DA, Verba KA, Jura N
Nature 600 339-343 (2021)
Related entries: 7mn5, 7mn6

Cited: 19 times
EuropePMC logo PMID: 34759323

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 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.

Reviews - 7mn8 mentioned but not cited (1)

  1. Cryo-electron Microscopic Analysis of Single-Pass Transmembrane Receptors. Cai K, Zhang X, Bai XC. Chem Rev 122 13952-13988 (2022)

Articles - 7mn8 mentioned but not cited (1)

  1. Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface. Diwanji D, Trenker R, Thaker TM, Wang F, Agard DA, Verba KA, Jura N. Nature 600 339-343 (2021)


Reviews citing this publication (5)

  1. Resistance to Trastuzumab. Vivekanandhan S, Knutson KL. Cancers (Basel) 14 5115 (2022)
  2. Sagacious epitope selection for vaccines, and both antibody-based therapeutics and diagnostics: tips from virology and oncology. Gan SK, Phua SX, Yeo JY. Antib Ther 5 63-72 (2022)
  3. The journey towards physiology and pathology: Tracing the path of neuregulin 4. Chen M, Zhu J, Luo H, Mu W, Guo L. Genes Dis 11 687-700 (2024)
  4. HER3 Alterations in Cancer and Potential Clinical Implications. Kilroy MK, Park S, Feroz W, Patel H, Mishra R, Alanazi S, Garrett JT. Cancers (Basel) 14 6174 (2022)
  5. Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System. Sotoyama H, Namba H, Tohmi M, Nawa H. Biomolecules 13 372 (2023)

Articles citing this publication (12)

  1. A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor. Huang Y, Ognjenovic J, Karandur D, Miller K, Merk A, Subramaniam S, Kuriyan J. Elife 10 e73218 (2021)
  2. A novel nanobody-based HER2-targeting antibody exhibits potent synergistic antitumor efficacy in trastuzumab-resistant cancer cells. Liu X, Luan L, Liu X, Jiang D, Deng J, Xu J, Yuan Y, Xing J, Chen B, Xing D, Huang H. Front Immunol 14 1292839 (2023)
  3. Allosteric activation of preformed EGF receptor dimers by a single ligand binding event. Purba ER, Saita EI, Akhouri RR, Öfverstedt LG, Wilken G, Skoglund U, Maruyama IN. Front Endocrinol (Lausanne) 13 1042787 (2022)
  4. An effective strategy for ligand-mediated pulldown of the HER2/HER3/NRG1β heterocomplex and cryo-EM structure determination at low sample concentrations. Trenker R, Diwanji D, Verba KA, Jura N. Methods Enzymol 667 633-662 (2022)
  5. Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention. Krimmer SG, Bertoletti N, Suzuki Y, Katic L, Mohanty J, Shu S, Lee S, Lax I, Mi W, Schlessinger J. Proc Natl Acad Sci U S A 120 e2300054120 (2023)
  6. Current status and future perspectives of bispecific antibodies in the treatment of lung cancer. Wang W, Qiu T, Li F, Ren S. Chin Med J (Engl) 136 379-393 (2023)
  7. Defucosylated Monoclonal Antibody (H2Mab-139-mG2a-f) Exerted Antitumor Activities in Mouse Xenograft Models of Breast Cancers against Human Epidermal Growth Factor Receptor 2. Suzuki H, Ohishi T, Nanamiya R, Kawada M, Kaneko MK, Kato Y. Curr Issues Mol Biol 45 7734-7748 (2023)
  8. Disentangling ERBB Signaling in Breast Cancer Subtypes-A Model-Based Analysis. Kemmer S, Berdiel-Acer M, Reinz E, Sonntag J, Tarade N, Bernhardt S, Fehling-Kaschek M, Hasmann M, Korf U, Wiemann S, Timmer J. Cancers (Basel) 14 2379 (2022)
  9. SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs. Li WJ, Xie CY, Zhu X, Tang J, Wang L, Lou LG. Acta Pharmacol Sin (2024)
  10. Structural arrangement of the active back-to-back dimer in N-glycosylated ErbB receptors is regulated by heterodimerization. Mashayekh-Poul R, Azimzadeh-Irani M, Masoomi-Nomandan SZ. Mol Biol Res Commun 12 95-107 (2023)
  11. Structure and dynamics of the EGFR/HER2 heterodimer. Bai X, Sun P, Wang X, Long C, Liao S, Dang S, Zhuang S, Du Y, Zhang X, Li N, He K, Zhang Z. Cell Discov 9 18 (2023)
  12. Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells. Galles GD, Infield DT, Clark CJ, Hemshorn ML, Manikandan S, Fazan F, Rasouli A, Tajkhorshid E, Galpin JD, Cooley RB, Mehl RA, Ahern CA. Nat Commun 14 59 (2023)


Quick links