EGF Activates Its Receptor by Removing Interactions that Autoinhibit Ectodomain Dimerization

Abstract

Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER) family receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation and are implicated in many human cancers. EGF activates its receptor by inducing dimerization of the 621 amino acid EGF receptor extracellular region. We describe the 2.8 A resolution crystal structure of this entire extracellular region (sEGFR) in an unactivated state. The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions. To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface. This contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists.

Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation

“…The events leading to dimerization of EGFR upon ligand binding are now well understood, as the crystal structure of the extracellular domain of EGFR bound to ligand has been solved (Garrett et al, 2002;Ogiso et al, 2002). Upon binding ligand, the extracellular domain changes conformation from a closed to an extended configuration, thereby freeing a dimerization loop and allowing receptor dimerization (Ogiso et al, 2002;Burgess et al, 2003;Ferguson et al, 2003) (see Figure 2). As the …”

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).…”

Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis

“…All EGFR receptors contain three different regions: an extracellular (ectodomain, ECD) ligand-binding region, a single membrane-spanning domain and a cytoplasmatic tyrosine kinase domain. The extracellular EGFR domains have been crystallographically elucidated by several research groups [3][4][5][6][7][8][9][10]. The x-ray structure-based models show the appearance of two large homologous domains (L) and two cysteinerich domains (CR), in the order L1-CR1-L2-CR2 which is simply known as I-II-III-IV domains, (see Scheme 1).…”