The epidermal growth factor (EGF) receptor is (as its name implies!) a receptor that sits at the surface of cell membranes. Like many other such receptors, its intracellular region contains a tyrosine kinase; the extracellular part binds to a small, soluble protein, epidermal growth factor (EGF). When EGF binds it stimulates a conformational change that leads to a dimerisation of two EGFR molecules. This activates the tyrosine kinases so they pass a signal - essentially saying "EGF has bound here" - through the cell in a cascade of phosphorylation reactions.
EGFR is one member of a family of four similar receptors, known as the ErbB family; it can also be known as ErbB1. You may have heard, indirectly, of another member of this family, ErbB2; this is over-expressed on the surface of breast cancer cells in about a quarter of breast cancers. It is the target of the drug herceptin, which has transformed the lives for many women with so-called "herceptin receptor positive" breast cancer.
This week, Professor Mark Lemmon from the University of Pennsylvania gave a seminar at University College, London, about the structural basis for the regulation of the EGF receptor. This was one of the regular seminars organised through the Institute of Structural Molecular Biology, which brings together researchers at Birkbeck and UCL working in structural biology, chemical biology, biophysics, proteomics and bioinformatics.
Lemmon's research is concerned with the structure of the extracellular, EGF-binding regions of these receptors. These are made up of four domains - two "L-domains" and two cysteine-rich domains, arranged in the order L-C-L-C starting from the N terminus of the protein. EGF binds between the two L-domains, and the two C-domains form the interface between the monomers in the dimer. In the absence of ligand, the extracellular region adopts a "tethered" conformation in which the dimerisation domain is occluded. However, this inactive, auto-inhibited conformation can also exist in the presence of EGF; Lemmon and colleagues solved the structure of the entire extracellular region, with ligand bound and in an inactive conformation (PDB file 1nql).
Lemmon and his colleagues have now studied the transition between the inactive, tethered state and the active, extended one using the technique of small-angle X-ray scattering (SAXS), which is used for observing large conformational changes in molecules. They found, importantly, that introducing mutations into the "tether" region of the protein cannot drive the transition to the active conformation. Rather, in this protein (but not in the apparently ligand-less herceptin receptor) it is only EGF binding that can cause the transition to the active form.
A useful (if a few years old) review of tyrosine kinase structure and function is Hubbard & Till (2000), Annu. Rev. Biochem. 69, 373-398. This is accessible from the Birkbeck e-library with your username and password.