Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/20685
Title: Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope.
Authors: Orellana, Laura;Thorne, Amy H;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, Modesto
Affiliation: Science for Life Laboratory, KTH Royal Institute of Technology, 17165 Solna, Sweden;. Department of Biochemistry and Biophysics, Stockholm University, 11419 Stockholm, Sweden
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0660
Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology, 08028 Barcelona, Catalonia, Spain
Department of Computational Science and Technology, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0660
Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology, 08028 Barcelona, Catalonia, Spain
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal
Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, 34090 Montpellier, France
Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology, 08028 Barcelona, Catalonia, Spain
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0660
Department of Biochemistry and Biomedicine, University of Barcelona, 08028 Barcelona, Catalonia, Spain
School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia
Science for Life Laboratory, KTH Royal Institute of Technology, 17165 Solna, Sweden
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Biochemistry and Biophysics, Stockholm University, 11419 Stockholm, Sweden
Issue Date: 26-Apr-2019
EDate: 2019-05-14
Citation: Proceedings of the National Academy of Sciences of the United States of America 2019; 116(20): 10009-10018
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20685
DOI: 10.1073/pnas.1821442116
ORCID: 0000-0003-1927-555X
0000-0003-2663-3220
0000-0003-3804-9179
0000-0003-1909-4361
0000-0002-6656-295X
PubMed URL: 31028138
Type: Journal Article
Subjects: cancer
cryptoepitope
intermediate
mutational heterogeneity
structural convergence
Appears in Collections:Journal articles

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