Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/150833
Title: Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
Author: Orellana, Laura
Thorne, Aamy
Lema, Rafael
Gustavsson, Johan
Parisian, Alison D.
Hospital, Adam
Cordeiro, Tiago N.
Bernadó, Pau
Scott, Andrew M.
Brun-Heath, Isabelle
Lindahl, Erik
Cavenee, Webster K.
Furnari, Frank B.
Orozco López, Modesto
Keywords: Epidermis
Càncer
Epidermis
Cancer
Issue Date: 26-Apr-2019
Publisher: National Academy of Sciences
Abstract: Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.
Note: Reproducció del document publicat a: https://doi.org/10.1073/pnas.1821442116
It is part of: Proceedings of the National Academy of Sciences of the United States of America - PNAS, 2019, vol. 116, num. 20, p. 10009-10018
URI: http://hdl.handle.net/2445/150833
Related resource: https://doi.org/10.1073/pnas.1821442116
ISSN: 0027-8424
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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