Title : Structural evidence for loose linkage between ligand binding and
kinase activation in the
epidermal growth factor receptor
Abstract :
- The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling are largely unknown for receptors with single-pass transmembrane domains such as the epidermal growth factor receptor ( EGFR )
- A crystal structure of the extracellular domain of EGFR dimerized by epidermal growth factor ( EGF ) reveals the extended, rod-like domain IV and a small, hydrophobic domain IV interface compatible with flexibility
- The crystal structure and disulfide cross-linking suggest that the 7-residue linker between the extracellular and transmembrane domains is flexible
- Disulfide cross-linking of the transmembrane domain shows that EGF stimulates only moderate association in the first two α-helical turns, in contrast to association throughout the membrane over five α-helical turns in glycophorin A and integrin
- Furthermore, systematic mutagenesis to leucine and phenylalanine suggests that no specific transmembrane interfaces are required for EGFR kinase activation
- These results suggest that linkage between ligand-induced dimerization and tyrosine kinase activation is much looser than was previously envisioned