Abstract
Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain.
Highlights
Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation
Subsequent EGFR signalling across the plasma membrane depends on an allosteric interaction between an activator and receiver kinase effected through an asymmetric tyrosine kinase domain (TKD) dimer[10]
Multiple separations >20 nm and periodic DIII–DIII components report ligand-free wild-type EGFR (wtEGFR) oligomers larger than dimers and stoichiometric extracellular interactions, respectively. These results agree with previous data from T47D cells[28], which express 10-fold fewer EGFR copies/cell, indicating that the ligand-free structures formed by EGFR are independent of receptor expression
Summary
Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. It is widely believed that autoinhibition is related to the adoption of an inactive symmetric TKD (sTKD) dimer revealed by X-ray structures of EGFR TKDs bearing the V924R (or V948R) and I682Q mutations at the C-lobe and N-lobe, which inhibit aTKD dimer formation Molecular dynamics (MD) simulations[23] suggested that the sTKD dimer is coupled via a C-crossing TM domain dimer to a ligand-free back-to-back dimer analogous to the X-ray structure of the Drosophila ECM dimer[24] and a model based on a ECM
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