title: Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region.
abstract: Binding of transforming growth factor α (TGF-α) to the epidermal growth factor receptor (EGFR) extracellular domain is encoded through the formation of a unique antiparallel coiled coil within the juxtamembrane segment. This new coiled coil is an "inside-out" version of the coiled coil formed in the presence of epidermal growth factor (EGF). A third, intermediary coiled-coil interface is formed in the juxtamembrane region when EGFR is stimulated with betacellulin. The seven growth factors that activate EGFR in mammalian systems (EGF, TGF-α, epigen, epiregulin, betacellulin, heparin-binding EGF, and amphiregulin) fall into distinct categories in which the structure of the coiled coil induced within the juxtamembrane region correlates with cell state. The observation that coiled-coil state tracks with the downstream signaling profiles for each ligand provides evidence for growth factor functional selectivity by EGFR. Encoding growth factor identity in alternative coiled-coil rotamers provides a simple and elegant method for communicating chemical information across the plasma membrane.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Doerner
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Scheck
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, USA; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520-8103, USA. Electronic address: alanna.schepartz@yale.edu.
authors.forename: Alanna
authors.initials: A
authors.lastname: Schepartz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D066259:Betacellulin / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: D066259:Betacellulin; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors