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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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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. |
format | Online Article Text |
id | pubmed-7452315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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