Oncogenic mutations of the EGF-Receptor ectodomain reveal an unexpected mechanism for ligand-independent activation

TitleOncogenic mutations of the EGF-Receptor ectodomain reveal an unexpected mechanism for ligand-independent activation
Publication TypeJournal Article
Year of Publication2014
AuthorsOrellana, Laura, Hospital Adam, and Orozco Modesto
JournalbioRxiv
Date Published09/2014
Abstract

Epidermal Growth Factor Receptor (EGFR) signalling is supposed to be triggered by a ligand-induced conformational change of the extracellular domain from a closed, self-inhibited tethered monomer, to an open untethered state with a free dimerization arm. The ectodomain also untethers spontaneously, but the molecular mechanism is still unknown. Experiments with the mAb806 antibody have suggested the existence of a third untethered state, still uncharacterised, appearing transiently during the tethered to untethered transition, and which exposes a cryptic epitope hidden in the known conformers. Here, simulations of two ectodomain mutants (R84K and G39R) targeting a domain I-II hinge reveal a new untethered but compact conformation, which originates from a back-rotation of domain I exposing the mAb806 epitope as the EGFRvIII deletion does. The present findings point to different molecular processes for ligand-dependent and spontaneous untethering, and suggest that point mutations and the EGFRvIII deletion may share a common activation mechanism related to domain I positioning.

URLhttp://biorxiv.org/content/early/2014/09/16/009068.abstract
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