The Crystal Structure of a Truncated ErbB2 Ectodomain Reveals an Active Conformation, Poised to Interact with Other ErbB Receptors

Abstract

ErbB2 does not bind ligand, yet appears to be the major signaling partner for other ErbB receptors by forming heteromeric complexes with ErbB1, ErbB3, or ErbB4. The crystal structure of residues 1-509 of ErbB2 at 2.5 A resolution reveals an activated conformation similar to that of the EGFR when complexed with ligand and very different from that seen in the unactivated forms of ErbB3 or EGFR. The structure explains the inability of ErbB2 to bind known ligands and suggests why ErbB2 fails to form homodimers. Together, the data suggest a model in which ErbB2 is already in the activated conformation and ready to interact with other ligand-activated ErbB receptors.

The ERBB3 receptor in cancer and cancer gene therapy

“…As a result the comparable configuration in ERBB3 is wider, suggesting that additional events may be needed for ligand action, or that two molecules of ligand could bind simultaneously. 48,50,51 (4) The latter interpretation is supported by the observation that constitutively locked ERBB3 bound ligand as well as did the extended conformation. 52 (5) ERBB3 does not form stable, ligand-bound homo-dimers, 53 in contrast to EGFR.…”

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…However, the hypothesized HER2 ligand was never discovered, and biochemical screens, post-genome computional studies and crystal structure revelations have made it clear that HER2 has no physiologic ligand, and that its ligand responsive functions are mediated through heterodimerization with its ligand-activated HER family partners (Sliwkowski, 2003). In fact, the extracellular domain of HER2 constitutively exists in an active conformation resembling the ligand-bound state of the other HER family proteins, precluding any potential activating role for ligands (Cho et al, 2003;Garrett et al, 2003). Therefore, the hypothesis that trastuzumab inhibits direct ligand binding and activation of HER2 is all but dismissed at this point.…”

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

“…However, HER2 possesses tyrosine kinase activity, and seems to be the major signaling partner for EGFR family members through the formation of heteromeric complexes (2). Heterodimerization between two EGFR family members requires ligand binding (3,4), but the crystal structure of a truncated HER2 ectodomain suggests that HER2 is constitutively in the activated conformation and readily interacts with HER3 mostly and other EGFR family members (5). Overexpression of HER2 promotes ligand-independent formation of a HER2/HER3 receptor complex, a major oncogenic driver in HER2-overexpressing breast tumor cells (6).…”