title: Negative co-operativity in the EGF receptor.
abstract: Scatchard analyses of the binding of EGF (epidermal growth factor) to its receptor (EGFR) yield concave up Scatchard plots, indicative of some type of heterogenity in ligand-binding affinity. This was typically interpreted as being due to the presence of two independent binding sites: one of high affinity representing ≤10% of the receptor population, and one of low affinity making up the bulk of the receptors. However, the concept of two independent binding sites is difficult to reconcile with the X-ray structures of the dimerized EGFR that show symmetrical binding of the two ligands. A new approach to the analysis of 125I-EGF-binding data combined with the structure of the singly-occupied Drosophila EGFR have now shown that this heterogeneity is due to the presence of negative co-operativity in the EGFR. Concerns that negative co-operativity precludes ligand-induced dimerization of the EGFR confuse the concepts of linkage and co-operativity. Linkage refers to the effect of ligand on the assembly of dimers, whereas co-operativity refers to the effect of ligand binding to one subunit on ligand binding to the other subunit within a preassembled dimer. Binding of EGF to its receptor is positively linked with dimer assembly, but shows negative co-operativity within the dimer.
authors.affiliation: Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 So. Euclid, Box 8231, St. Louis, MO 63110, USA. pike@biochem.wustl.edu
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Pike
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors