Two EGF molecules contribute additively to stabilization of the EGFR dimer.
Receptor dimerization is generally considered to be the primary signaling 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 human growth hormone (hGH) receptor. We have analyzed the binding of epidermal growth factor (EGF) to the extracellular domain of its receptor (sEGFR) using titration calorimetry, and the resulting dimerization of sEGFR using small-angle X-ray scattering. EGF induces the quantitative formation of sEGFR dimers that contain two EGF molecules. The data obtained from the two approaches suggest a model in which one EGF monomer binds to one sEGFR monomer, and that receptor dimerization involves subsequent association of two monomeric (1:1) EGF-sEGFR complexes. Dimerization may result from bivalent binding of both EGF molecules in the dimer and/or receptor-receptor interactions. The requirement for two (possibly bivalent) EGF monomers distinguishes EGF-induced sEGFR dimerization from the hGH and interferon-gamma receptors, where multivalent binding of a single ligand species (either monomeric or dimeric) drives receptor oligomerization. The proposed model of EGF-induced sEGFR dimerization suggests possible mechanisms for both ligand-induced homo- and heterodimerization of the EGFR (or erbB) family of receptors.
Lemmon
M A
MA
Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
Bu
Z
Z
Ladbury
J E
JE
Zhou
M
M
Pinchasi
D
D
Lax
I
I
Engelman
D M
DM
Schlessinger
J
J
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000737:chemistry* / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D011487:Protein Conformation; D012542:Scattering, Radiation; D013329:Structure-Activity Relationship
D004815:Epidermal Growth Factor; D066246:ErbB Receptors