Transmembrane domain of the Epidermal Growth Factor Receptor family of Protein Tyrosine Kinases
PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER, ErbB) subfamily members include EGFR (HER1, ErbB1), HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), and similar proteins. They are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane (TM) helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. They are activated by ligand-induced dimerization, resulting in the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Collectively, they can recognize a variety of ligands including EGF, TGFalpha, and neuregulins, among others. All four subfamily members can form homo- or heterodimers. HER3 contains an impaired kinase domain and depends on its heterodimerization partner for activation. EGFR subfamily members are involved in signaling pathways leading to a broad range of cellular responses including cell proliferation, differentiation, migration, growth inhibition, and apoptosis. The TM domain not only serves as a membrane anchor, but also plays an important role in receptor dimerization and optimal activation. Mutations in the TM domain of EGFR family RTKs have been associated with increased breast cancer risk.
Comment:ErbB receptors are activated via ligand-induced dimerization. All ErbB receptors can form homo- and heterodimers. The TM domain plays an important role in dimerization and optimal activation.
Structure:2KS1: Human ErbB2 TM domain forms a heterodimer with ErbB1 TM domain; contacts at 4A. - View structure with Cn3D
Structure:2L2T: Human ErbB4 TM domain forms a homodimer; contacts at 4A. - View structure with Cn3D
Structure:2JWA: Human ErbB2 TM domain forms a homodimer; contacts at 4A. - View structure with Cn3D
Structure:2L9U: Human ErbB3 TM domain forms a homodimer; contacts at 4A. - View structure with Cn3D
Jiyao W et al.(2023). "The conserved domain database in 2023.",