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Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands

Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally...

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Autores principales: Brahimi, Fouad, Galan, Alba, Jmaeff, Sean, Barcelona, Pablo F., De Jay, Nicolas, Dejgaard, Kurt, Young, Jason C., Kleinman, Claudia L., Thomas, David Y., Saragovi, H. Uri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452315/
https://www.ncbi.nlm.nih.gov/pubmed/32829283
http://dx.doi.org/10.1016/j.isci.2020.101447
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author Brahimi, Fouad
Galan, Alba
Jmaeff, Sean
Barcelona, Pablo F.
De Jay, Nicolas
Dejgaard, Kurt
Young, Jason C.
Kleinman, Claudia L.
Thomas, David Y.
Saragovi, H. Uri
author_facet Brahimi, Fouad
Galan, Alba
Jmaeff, Sean
Barcelona, Pablo F.
De Jay, Nicolas
Dejgaard, Kurt
Young, Jason C.
Kleinman, Claudia L.
Thomas, David Y.
Saragovi, H. Uri
author_sort Brahimi, Fouad
collection PubMed
description Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse 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 ligands NT-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 heterogeneity in receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.
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spelling pubmed-74523152020-08-31 Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands Brahimi, Fouad Galan, Alba Jmaeff, Sean Barcelona, Pablo F. De Jay, Nicolas Dejgaard, Kurt Young, Jason C. Kleinman, Claudia L. Thomas, David Y. Saragovi, H. Uri iScience Article Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse 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 ligands NT-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 heterogeneity in receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms. Elsevier 2020-08-10 /pmc/articles/PMC7452315/ /pubmed/32829283 http://dx.doi.org/10.1016/j.isci.2020.101447 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brahimi, Fouad
Galan, Alba
Jmaeff, Sean
Barcelona, Pablo F.
De Jay, Nicolas
Dejgaard, Kurt
Young, Jason C.
Kleinman, Claudia L.
Thomas, David Y.
Saragovi, H. Uri
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452315/
https://www.ncbi.nlm.nih.gov/pubmed/32829283
http://dx.doi.org/10.1016/j.isci.2020.101447
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