Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands
Summary: 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 n...
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2020-09-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220306398 |
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doaj-a1ee55768c1b44989b14c88b23d6c5072020-11-25T03:30:30ZengElsevieriScience2589-00422020-09-01239101447Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional LigandsFouad Brahimi0Alba Galan1Sean Jmaeff2Pablo F. Barcelona3Nicolas De Jay4Kurt Dejgaard5Jason C. Young6Claudia L. Kleinman7David Y. Thomas8H. Uri Saragovi9Lady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, CanadaLady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, CanadaLady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, Canada; Department of Pharmacology, McGill University, Montreal, QC, CanadaLady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, CanadaLady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC, CanadaDepartment of Biochemistry, McGill University, Montreal, QC, CanadaDepartment of Biochemistry, McGill University, Montreal, QC, CanadaLady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC, CanadaDepartment of Biochemistry, McGill University, Montreal, QC, CanadaLady Davis Institute-Jewish General Hospital, McGill University, 3755 Côte St. Catherine, E-535, Montreal, QC H3T 1E2, Canada; Department of Pharmacology, McGill University, Montreal, QC, Canada; Department of Ophthalmology and Visual Science, McGill University, Montreal, QC, Canada; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220306398Biological SciencesBiochemistryStructural Biology |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Fouad Brahimi Alba Galan Sean Jmaeff Pablo F. Barcelona Nicolas De Jay Kurt Dejgaard Jason C. Young Claudia L. Kleinman David Y. Thomas H. Uri Saragovi |
| spellingShingle |
Fouad Brahimi Alba Galan Sean Jmaeff Pablo F. Barcelona Nicolas De Jay Kurt Dejgaard Jason C. Young Claudia L. Kleinman David Y. Thomas H. Uri Saragovi Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands iScience Biological Sciences Biochemistry Structural Biology |
| author_facet |
Fouad Brahimi Alba Galan Sean Jmaeff Pablo F. Barcelona Nicolas De Jay Kurt Dejgaard Jason C. Young Claudia L. Kleinman David Y. Thomas H. Uri Saragovi |
| author_sort |
Fouad Brahimi |
| title |
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_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 |
| publisher |
Elsevier |
| series |
iScience |
| issn |
2589-0042 |
| publishDate |
2020-09-01 |
| description |
Summary: 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. |
| topic |
Biological Sciences Biochemistry Structural Biology |
| url |
http://www.sciencedirect.com/science/article/pii/S2589004220306398 |
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