Open AccessPhosphorylation-Dependent Conformations of the Disordered Carboxyl-Terminus Domain in the Epidermal Growth Factor Receptor
Author(s) -
Raju Regmi,
Shwetha Srinivasan,
A. J. H. Latham,
Vandna Kukshal,
Weidong Cui,
Bin Zhang,
Ron Bose,
Gabriela S. SchlauCohen
Publication year - 2020
Publication title -
the journal of physical chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.563
H-Index - 203
ISSN - 1948-7185
DOI - 10.1021/acs.jpclett.0c02327
Subject(s) - autophosphorylation , phosphorylation , biophysics , tyrosine , chemistry , epidermal growth factor receptor , docking (animal) , epidermal growth factor , intrinsically disordered proteins , receptor tyrosine kinase , protein kinase domain , tyrosine phosphorylation , receptor , microbiology and biotechnology , biochemistry , biology , protein kinase a , mutant , medicine , nursing , gene
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.