Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands

Autores
Brahimi, Fouad; Galan, Alba; Jmaeff, Sean; Barcelona, Pablo Federico; De Jay, Nicolas; Dejgaard, Kurt; Young, Jason C.; Kleinman, Claudia Laura; Thomas, David Y.; Saragovi, H. Uri
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated there verse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms(TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligandsNT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways,whereas PTP-sigma activates biased signals. Our data support an "in-to-out" model controlling receptor ectodomain conformation, a strategy that enables heterogeneityin receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.
Fil: Brahimi, Fouad. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: De Jay, Nicolas. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Dejgaard, Kurt. McGill University; Canadá
Fil: Young, Jason C.. McGill University; Canadá
Fil: Kleinman, Claudia Laura. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Thomas, David Y.. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
Materia
TrkC-FL
TrkC.T1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/158658
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/158658
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional LigandsBrahimi, FouadGalan, AlbaJmaeff, SeanBarcelona, Pablo FedericoDe Jay, NicolasDejgaard, KurtYoung, Jason C.Kleinman, Claudia LauraThomas, David Y.Saragovi, H. UriTrkC-FLTrkC.T1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated there verse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms(TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligandsNT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways,whereas PTP-sigma activates biased signals. Our data support an "in-to-out" model controlling receptor ectodomain conformation, a strategy that enables heterogeneityin receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.Fil: Brahimi, Fouad. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: De Jay, Nicolas. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Dejgaard, Kurt. McGill University; CanadáFil: Young, Jason C.. McGill University; CanadáFil: Kleinman, Claudia Laura. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Thomas, David Y.. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; CanadáBellwether Publ Ltd2020-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/158658Brahimi, Fouad; Galan, Alba; Jmaeff, Sean; Barcelona, Pablo Federico; De Jay, Nicolas; et al.; Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands; Bellwether Publ Ltd; Giscience & Remote Sensing; 23; 9; 8-2020; 1-341548-16031943-7226CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.isci.2020.101447info:eu-repo/semantics/altIdentifier/url/https://www.cell.com/iscience/fulltext/S2589-0042(20)30639-8info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:21:58Zoai:ri.conicet.gov.ar:11336/158658instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:21:59.329CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
title Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
spellingShingle Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
Brahimi, Fouad
TrkC-FL
TrkC.T1
title_short Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
title_full Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
title_fullStr Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
title_full_unstemmed Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
title_sort Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands
dc.creator.none.fl_str_mv Brahimi, Fouad
Galan, Alba
Jmaeff, Sean
Barcelona, Pablo Federico
De Jay, Nicolas
Dejgaard, Kurt
Young, Jason C.
Kleinman, Claudia Laura
Thomas, David Y.
Saragovi, H. Uri
author Brahimi, Fouad
author_facet Brahimi, Fouad
Galan, Alba
Jmaeff, Sean
Barcelona, Pablo Federico
De Jay, Nicolas
Dejgaard, Kurt
Young, Jason C.
Kleinman, Claudia Laura
Thomas, David Y.
Saragovi, H. Uri
author_role author
author2 Galan, Alba
Jmaeff, Sean
Barcelona, Pablo Federico
De Jay, Nicolas
Dejgaard, Kurt
Young, Jason C.
Kleinman, Claudia Laura
Thomas, David Y.
Saragovi, H. Uri
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TrkC-FL
TrkC.T1
topic TrkC-FL
TrkC.T1
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated there verse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms(TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligandsNT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways,whereas PTP-sigma activates biased signals. Our data support an "in-to-out" model controlling receptor ectodomain conformation, a strategy that enables heterogeneityin receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.
Fil: Brahimi, Fouad. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: De Jay, Nicolas. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Dejgaard, Kurt. McGill University; Canadá
Fil: Young, Jason C.. McGill University; Canadá
Fil: Kleinman, Claudia Laura. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Thomas, David Y.. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
description Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated there verse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms(TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligandsNT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways,whereas PTP-sigma activates biased signals. Our data support an "in-to-out" model controlling receptor ectodomain conformation, a strategy that enables heterogeneityin receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.
publishDate 2020
dc.date.none.fl_str_mv 2020-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/158658
Brahimi, Fouad; Galan, Alba; Jmaeff, Sean; Barcelona, Pablo Federico; De Jay, Nicolas; et al.; Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands; Bellwether Publ Ltd; Giscience & Remote Sensing; 23; 9; 8-2020; 1-34
1548-1603
1943-7226
CONICET Digital
CONICET
url http://hdl.handle.net/11336/158658
identifier_str_mv Brahimi, Fouad; Galan, Alba; Jmaeff, Sean; Barcelona, Pablo Federico; De Jay, Nicolas; et al.; Alternative splicing of a receptor Intracellular domain yields different ectodomain conformations, enabling Isoform-Selective Functional Ligands; Bellwether Publ Ltd; Giscience & Remote Sensing; 23; 9; 8-2020; 1-34
1548-1603
1943-7226
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.isci.2020.101447
info:eu-repo/semantics/altIdentifier/url/https://www.cell.com/iscience/fulltext/S2589-0042(20)30639-8
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Bellwether Publ Ltd
publisher.none.fl_str_mv Bellwether Publ Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846082613363605504
score 13.22299

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