Bipartite tetracysteine display reveals allosteric control of ligand-specific EGFR activation.
Aberrant activation of the epidermal growth factor receptor (EGFR), a prototypic receptor tyrosine kinase, is critical to the biology of many common cancers. The molecular events that define how EGFR transmits an extracellular ligand binding event through the membrane are not understood. Here we use a chemical tool, bipartite tetracysteine display, to report on ligand-specific conformational changes that link ligand binding and kinase activation for full-length EGFR on the mammalian cell surface. We discover that EGF binding is communicated to the cytosol through formation of an antiparallel coiled coil within the intracellular juxtamembrane (JM) domain. This conformational transition is functionally coupled to receptor activation by EGF. In contrast, TGFα binding is communicated to the cytosol through formation of a discrete, alternative helical interface. These findings suggest that the JM region can differentially decode extracellular signals and transmit them to the cell interior. Our results provide new insight into how EGFR communicates ligand-specific information across the membrane.
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, USA.
Rebecca A
RA
Scheck
Melissa A
MA
Lowder
Jacob S
JS
Appelbaum
Alanna
A
Schepartz
D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003545:Cysteine / Q000737:chemistry*; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000737:chemistry; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D008024:Ligands; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D003545:Cysteine