Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope

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 gliob...

Descripción completa

Detalles Bibliográficos
Autores: Orellana, Laura, Thorne, Aamy, Lema, Rafael, Gustavsson, Johan, Parisian, Alison D., Hospital, Adam, Cordeiro, Tiago N., Bernadó Peretó, Pau, Scott, Andrew M., Brun Heath, Isabelle, Lindahl, Erik, Cavenee, Webster K., Furnari, Frank B., Orozco López, Modesto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/150833
Acceso en línea:https://hdl.handle.net/2445/150833
Access Level:acceso abierto
Palabra clave:Epidermis
Càncer
Cancer
id ES_3ed135b8e65be88d5a8e942e5f5d2e5c
oai_identifier_str oai:recercat.cat:2445/150833
network_acronym_str ES
network_name_str España
repository_id_str
spelling Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitopeOrellana, LauraThorne, AamyLema, RafaelGustavsson, JohanParisian, Alison D.Hospital, AdamCordeiro, Tiago N.Bernadó Peretó, PauScott, Andrew M.Brun Heath, IsabelleLindahl, ErikCavenee, Webster K.Furnari, Frank B.Orozco López, ModestoEpidermisCàncerEpidermisCancerEpidermal 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.National Academy of Sciences2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion10 p.application/pdfhttps://hdl.handle.net/2445/150833Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1073/pnas.1821442116Proceedings of the National Academy of Sciences of the United States of America - PNAS, 2019, vol. 116, num. 20, p. 10009-10018https://doi.org/10.1073/pnas.1821442116info:eu-repo/grantAgreement/EC/H2020/823830(c) Orellana, Laura et al., 2019info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1508332026-05-29T05:05:01Z
dc.title.none.fl_str_mv Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
title Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
spellingShingle Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
Orellana, Laura
Epidermis
Càncer
Epidermis
Cancer
title_short Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
title_full Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
title_fullStr Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
title_full_unstemmed Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
title_sort Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
dc.creator.none.fl_str_mv Orellana, Laura
Thorne, Aamy
Lema, Rafael
Gustavsson, Johan
Parisian, Alison D.
Hospital, Adam
Cordeiro, Tiago N.
Bernadó Peretó, Pau
Scott, Andrew M.
Brun Heath, Isabelle
Lindahl, Erik
Cavenee, Webster K.
Furnari, Frank B.
Orozco López, Modesto
author Orellana, Laura
author_facet Orellana, Laura
Thorne, Aamy
Lema, Rafael
Gustavsson, Johan
Parisian, Alison D.
Hospital, Adam
Cordeiro, Tiago N.
Bernadó Peretó, Pau
Scott, Andrew M.
Brun Heath, Isabelle
Lindahl, Erik
Cavenee, Webster K.
Furnari, Frank B.
Orozco López, Modesto
author_role author
author2 Thorne, Aamy
Lema, Rafael
Gustavsson, Johan
Parisian, Alison D.
Hospital, Adam
Cordeiro, Tiago N.
Bernadó Peretó, Pau
Scott, Andrew M.
Brun Heath, Isabelle
Lindahl, Erik
Cavenee, Webster K.
Furnari, Frank B.
Orozco López, Modesto
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Epidermis
Càncer
Epidermis
Cancer
topic Epidermis
Càncer
Epidermis
Cancer
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/150833
url https://hdl.handle.net/2445/150833
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1073/pnas.1821442116
Proceedings of the National Academy of Sciences of the United States of America - PNAS, 2019, vol. 116, num. 20, p. 10009-10018
https://doi.org/10.1073/pnas.1821442116
info:eu-repo/grantAgreement/EC/H2020/823830
dc.rights.none.fl_str_mv (c) Orellana, Laura et al., 2019
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Orellana, Laura et al., 2019
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406584740773888
score 15,812429

Similares en LA Referencia