Epidermal growth factor (EGF) induces oligomerization of soluble, extracellular, ligand-binding domain of EGF receptor. A low resolution projection structure of the ligand-binding domain.
Ligand-induced oligomerization is a universal phenomenon among growth factor receptors. Although the mechanism involved is yet to be defined, much evidence indicates that receptor oligomerization plays a crucial role in receptor activation and signal transduction. Here we show that epidermal growth factor (EGF) is able to stimulate the oligomerization of a recombinant, soluble, extracellular ligand-binding domain of EGF receptor. Covalent cross-linking experiments, analysis by sodium dodecyl sulfate-gel electrophoresis, size exclusion chromatography, and electron microscopy demonstrate that receptor dimers, trimers and larger multimers are formed in response to EGF. This establishes that receptor oligomerization is an intrinsic property of the extracellular ligand-binding domain of EGF receptor. Ligand-induced conformational change in the extracellular domain will stimulate receptor-receptor interactions. This may bring about the allosteric change involved in signal transduction from the extracellular domain across the plasma membrane, resulting in the activation of the cytoplasmic kinase domain. Electron microscopic images of individual extracellular ligand-binding domains appear as clusters of four similarly-sized stain-excluding areas arranged around a central, relatively less stain-excluded area. This suggests that the extracellular ligand-binding domain is structurally composed of four separate domains.
Lax
I
I
Department of Pharmacology, New York University Medical Center, New York 10016.
Mitra
A K
AK
Ravera
C
C
Hurwitz
D R
DR
Rubinstein
M
M
Ullrich
A
A
Stroud
R M
RM
Schlessinger
J
J
D001483:Base Sequence; D001665:Binding Sites; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D005110:Extracellular Space; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D011485:Protein Binding; D011940:Receptor Aggregation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D046911:Macromolecular Substances; D009841:Oligonucleotides; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors