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Cell Chem Biol. 2018 Jul 19;25(7):857-870.e7. doi: 10.1016/j.chembiol.2018.04.005. Epub 2018 May 3.

Mechanism of Allosteric Coupling into and through the Plasma Membrane by EGFR.

Author information

1
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
2
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520-8103, USA. Electronic address: alanna.schepartz@yale.edu.

Abstract

Epidermal growth factor receptor (EGFR) interacts through its extracellular domain with seven different growth factors. These factors induce different structures within the cytoplasmic juxtamembrane (JM) segment of the dimeric receptor and propagate different growth factor-dependent signals to the cell interior. How this process occurs is unknown. Here we apply diverse experimental and computational tools to show that growth factor identity is encoded by the EGFR transmembrane (TM) helix into discrete helix dimer populations that differ in both cross-location and cross-angle. Helix dimers with smaller cross-angles at multiple cross locations are decoded to induce an EGF-type coiled coil in the adjacent JM, whereas helix dimers with larger cross-angles at fewer cross locations induce the TGF-α-type coiled coil. We propose an updated model for how conformational coupling across multiple EGFR domains results in growth factor-specific information transfer, and demonstrate that this model applies to both EGFR and the related receptor ErbB2.

KEYWORDS:

allostery; biased agonism; cancer; epidermal growth factor receptor (EGFR); information transfer; juxtamembrane domain; ligand-induced dimerization; receptor tyrosine kinase (RTK); signal transduction; transmembrane domain

PMID:
29731426
PMCID:
PMC6054568
DOI:
10.1016/j.chembiol.2018.04.005
[Indexed for MEDLINE]
Free PMC Article

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