Biophysical Evidence for Intrinsic Disorder in the C-terminal Tails of the Epidermal Growth Factor Receptor (EGFR) and HER3 Receptor Tyrosine Kinases
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The epidermal growth factor receptor (EGFR)/ErbB family of receptor tyrosine kinases includes oncogenes important in the progression of breast and other cancers, and they are targets for many drug development strategies. Each member of the ErbB family possesses a unique, structurally uncharacterized C-terminal tail that plays an important role in autophosphorylation and signal propagation. To determine whether these C-terminal tails are intrinsically disordered regions, we conducted a battery of biophysical experiments on the EGFR and HER3 tails. Using hydrogen/deuterium exchange mass spectrometry, we measured the conformational dynamics of intracellular half constructs and compared the tails with the ordered kinase domains. The C-terminal tails demonstrate more rapid deuterium exchange behavior when compared with the kinase domains. Next, we expressed and purified EGFR and HER3 tail-only constructs. Results from circular dichroism spectroscopy, size exclusion chromatography with multiangle light scattering, dynamic light scattering, analytical ultracentrifugation, and small angle X-ray scattering each provide evidence that the EGFR and HER3 C-terminal tails are intrinsically disordered with extended, non-globular structure in solution. The intrinsic disorder and extended conformation of these tails may be important for their function by increasing the capture radius and reducing the thermodynamic barriers for binding of downstream signaling proteins.
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Many receptors require intrinsically disordered cytoplasmic tails to function properly.
“Many receptors require intrinsically disordered cytoplasmic tails to function properly [169, 281–283].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [282]
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Sheetz, J. B., Tsutsui, Y., Ashtekar, K. D., Mathea, S., Knapp, S., & Lemmon, M. A. (2026) · Structure · doi:10.1016/j.str.2026.08.013
- Authors
- Keppel, T. R., Sarpong, K., Murray, E. M., Monsey, J., Zhu, J., & Bose, R.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Bose, Ron
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 292
- Issue
- 2
- Pages
- 597-610
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5241735
- OpenAlex
- W2556964862
- Cited by
- 29
- References
- 77
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 8 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 1
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Cancer Institute (R01 CA161001, 5T32 CA113275)
- National Institute of General Medical Sciences (8P41 GM103422)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- intrinsic disorder, intrinsically disordered regions, epidermal growth factor receptor, HER3, ErbB family, receptor tyrosine kinase, C-terminal tail, conformational dynamics, hydrogen-deuterium exchange, protein solution structure, autophosphorylation, signal transduction, binding thermodynamics
- MeSH terms
- Protein Domains, Circular Dichroism, Humans, Kinetics, X-Ray Diffraction, Receptor, ErbB-3, Deuterium Exchange Measurement, ErbB Receptors
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