Phosphorylation-Dependent Conformations of the Disordered Carboxyl-Terminus Domain in the Epidermal Growth Factor Receptor
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Regmi, Raju; Srinivasan, Shwetha; Latham, Andrew P; Kukshal, Vandna; Cui, Weidong; Zhang, Bin; Bose, Ron; Schlau-Cohen, Gabriela S; ... Show more Show less
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© 2020 American Chemical Society. All rights reserved. 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.
Date issued
2020Department
Massachusetts Institute of Technology. Department of ChemistryJournal
Journal of Physical Chemistry Letters
Publisher
American Chemical Society (ACS)
Citation
Regmi, Raju, Srinivasan, Shwetha, Latham, Andrew P, Kukshal, Vandna, Cui, Weidong et al. 2020. "Phosphorylation-Dependent Conformations of the Disordered Carboxyl-Terminus Domain in the Epidermal Growth Factor Receptor." Journal of Physical Chemistry Letters, 11 (23).
Version: Author's final manuscript