{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Regmi R"],"funding":["Richard and Susan Smith Family Foundation","Canadian Institute for Advanced Research","National Cancer Institute","Alfred P. Sloan Foundation","NCI NIH HHS","National Institute of General Medical Sciences","NIGMS NIH HHS","Arnold and Mabel Beckman Foundation"],"pagination":["10037-10044"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8063277"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11(23)"],"pubmed_abstract":["The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, regulates basic cellular functions and is a major target for anticancer therapeutics. The carboxyl-terminus domain is a disordered region of EGFR that contains the tyrosine residues, which undergo autophosphorylation followed by docking of signaling proteins. Local phosphorylation-dependent secondary structure has been identified and is thought to be associated with the signaling cascade. Deciphering and distinguishing the overall conformations, however, have been challenging because of the disordered nature of the carboxyl-terminus domain and resultant lack of well-defined three-dimensional structure for most of the domain. We investigated the overall conformational states of the isolated EGFR carboxyl-terminus domain using single-molecule Förster resonance energy transfer and coarse-grained simulations. Our results suggest that electrostatic interactions between charged residues emerge within the disordered domain upon phosphorylation, producing a looplike conformation. This conformation may enable binding of downstream signaling proteins and potentially reflect a general mechanism in which electrostatics transiently generate functional architectures in disordered regions of a well-folded protein."],"journal":["The journal of physical chemistry letters"],"pubmed_title":["Phosphorylation-Dependent Conformations of the Disordered Carboxyl-Terminus Domain in the Epidermal Growth Factor Receptor."],"pmcid":["PMC8063277"],"funding_grant_id":["DP2 GM128200","1R35GM133580-01","R01 CA161001","P41 GM103422","1DP2GM128200-01","8P41 GM103422","R35 GM133580"],"pubmed_authors":["Bose R","Kukshal V","Regmi R","Cui W","Srinivasan S","Latham AP","Schlau-Cohen GS","Zhang B"],"additional_accession":[]},"is_claimable":false,"name":"Phosphorylation-Dependent Conformations of the Disordered Carboxyl-Terminus Domain in the Epidermal Growth Factor Receptor.","description":"The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, regulates basic cellular functions and is a major target for anticancer therapeutics. The carboxyl-terminus domain is a disordered region of EGFR that contains the tyrosine residues, which undergo autophosphorylation followed by docking of signaling proteins. Local phosphorylation-dependent secondary structure has been identified and is thought to be associated with the signaling cascade. Deciphering and distinguishing the overall conformations, however, have been challenging because of the disordered nature of the carboxyl-terminus domain and resultant lack of well-defined three-dimensional structure for most of the domain. We investigated the overall conformational states of the isolated EGFR carboxyl-terminus domain using single-molecule Förster resonance energy transfer and coarse-grained simulations. Our results suggest that electrostatic interactions between charged residues emerge within the disordered domain upon phosphorylation, producing a looplike conformation. This conformation may enable binding of downstream signaling proteins and potentially reflect a general mechanism in which electrostatics transiently generate functional architectures in disordered regions of a well-folded protein.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Dec","modification":"2024-11-12T09:08:01.989Z","creation":"2022-02-09T16:09:39.069Z"},"accession":"S-EPMC8063277","cross_references":{"pubmed":["33179922"],"doi":["10.1021/acs.jpclett.0c02327"]}}