title: Conformational stability of the epidermal growth factor (EGF) receptor as influenced by glycosylation, dimerization and EGF hormone binding.
abstract: The epidermal growth factor receptor (EGFR) is an important transmembrane glycoprotein kinase involved the initiation or perpetuation of signal transduction cascades within cells. These processes occur after EGFR binds to a ligand [epidermal growth factor (EGF)], thus inducing its dimerization and tyrosine autophosphorylation. Previous publications have highlighted the importance of glycosylation and dimerization for promoting proper function of the receptor and conformation in membranes; however, the effects of these associations on the protein conformational stability have not yet been described. Molecular dynamics simulations were performed to characterize the conformational preferences of the monomeric and dimeric forms of the EGFR extracellular domain upon binding to EGF in the presence and absence of N-glycan moieties. Structural stability analyses revealed that EGF provides the most conformational stability to EGFR, followed by glycosylation and dimerization, respectively. The findings also support that EGF-EGFR binding takes place through a large-scale induced-fitting mechanism. Proteins 2017; 85:561-570. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Geology, Kent State University, North Canton, Ohio, 44720.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Taylor
authors.affiliation: Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Recife, Pernambuco, 50740-465, Brazil.|Department of Fundamental Chemistry, Federal University of Pernambuco, Recife, Pernambuco, 50740-560, Brazil.
authors.forename: Laercio
authors.identifier: 0000-0002-4621-3031
authors.initials: L
authors.lastname: Pol-Fachin
authors.affiliation: Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Recife, Pernambuco, 50740-465, Brazil.|Department of Fundamental Chemistry, Federal University of Pernambuco, Recife, Pernambuco, 50740-560, Brazil.
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Lins
authors.affiliation: School of Environment and Natural Resources, Ohio State University, 275 Mendenhall Laboratory, Columbus, Ohio, 43210.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Lower
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry*; D001216:Asparagine / Q000737:chemistry*; D001665:Binding Sites; D004815:Epidermal Growth Factor / Q000737:chemistry*; D066246:ErbB Receptors / Q000737:chemistry*; D006031:Glycosylation; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D004815:Epidermal Growth Factor; D001216:Asparagine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000117:Acetylglucosamine
keywords: EGF binding; ErbB; glycoprotein; molecular dynamics