Journal
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 11, Issue 23, Pages 10037-10044Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.0c02327
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Funding
- NIH Director's New Innovator Award [1DP2GM128200-01]
- Beckman Young investigator Award
- National Institutes of Health [R01 CA161001, 8P41 GM103422, 1R35GM133580-01]
- National Science Foundation Graduate Research Fellowship Program
- Sloan Research Fellowship in Chemistry
- Smith Family Award for Excellence in Biomedical Research
- CIFAR Global Scholar Award
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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 Forster 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.
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