2 EGF MOLECULES CONTRIBUTE ADDITIVELY TO STABILIZATION OF THE EGFR DIMER

Receptor dimerization is generally considered to be the primary signal ing event upon binding of a growth factor to its receptor at the cell surface, Little, however, is known about the precise molecular details of ligand-induced receptor dimerization, except for studies of the hu man growth hormone (hGH) receptor, We have analyzed the binding of epi dermal growth factor (EGF) to the extracellular domain of its receptor (sEGFR) using titration calorimetry, and the resulting dimerization o f sEGFR using small-angle X-ray scattering, EGF induces the quantitati ve formation of sEGFR dimers that contain two EGF molecules, The data obtained from the two approaches suggest a model in which one EGF mono mer binds to one sEGFR monomer, and that receptor dimerization involve s subsequent association of two monomeric (1:1) EGF-sEGFR complexes, D imerization may result from bivalent binding of both EGF molecules in the dimer and/or receptor-receptor interactions, The requirement for t wo (possibly bivalent) EGF monomers distinguishes EGF-induced sEGFR di merization from the hGH and interferon-gamma receptors, where multival ent binding of a single ligand species (either monomeric or dimeric) d rives receptor oligomerization. The proposed model of EGF-induced sEGF R dimerization suggests possible mechanisms for both ligand-induced ho mo- and heterodimerization of the EGFR (or erbB) family of receptors.