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Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker
Eph receptor tyrosine kinases play a key role in cell-cell communication. Lack of structural information on the entire multi-domain intracellular region of any Eph receptor has hindered understanding of their signaling mechanisms. Here, we use integrative structural biology to investigate the struct...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639986/ https://www.ncbi.nlm.nih.gov/pubmed/34857764 http://dx.doi.org/10.1038/s41467-021-27343-z |
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author | Lechtenberg, Bernhard C. Gehring, Marina P. Light, Taylor P. Horne, Christopher R. Matsumoto, Mike W. Hristova, Kalina Pasquale, Elena B. |
author_facet | Lechtenberg, Bernhard C. Gehring, Marina P. Light, Taylor P. Horne, Christopher R. Matsumoto, Mike W. Hristova, Kalina Pasquale, Elena B. |
author_sort | Lechtenberg, Bernhard C. |
collection | PubMed |
description | Eph receptor tyrosine kinases play a key role in cell-cell communication. Lack of structural information on the entire multi-domain intracellular region of any Eph receptor has hindered understanding of their signaling mechanisms. Here, we use integrative structural biology to investigate the structure and dynamics of the EphA2 intracellular region. EphA2 promotes cancer malignancy through a poorly understood non-canonical form of signaling involving serine/threonine phosphorylation of the linker connecting its kinase and SAM domains. We show that accumulation of multiple linker negative charges, mimicking phosphorylation, induces cooperative changes in the EphA2 intracellular region from more closed to more extended conformations and perturbs the EphA2 juxtamembrane segment and kinase domain. In cells, linker negative charges promote EphA2 oligomerization. We also identify multiple kinases catalyzing linker phosphorylation. Our findings suggest multiple effects of linker phosphorylation on EphA2 signaling and imply that coordination of different kinases is necessary to promote EphA2 non-canonical signaling. |
format | Online Article Text |
id | pubmed-8639986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86399862021-12-15 Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker Lechtenberg, Bernhard C. Gehring, Marina P. Light, Taylor P. Horne, Christopher R. Matsumoto, Mike W. Hristova, Kalina Pasquale, Elena B. Nat Commun Article Eph receptor tyrosine kinases play a key role in cell-cell communication. Lack of structural information on the entire multi-domain intracellular region of any Eph receptor has hindered understanding of their signaling mechanisms. Here, we use integrative structural biology to investigate the structure and dynamics of the EphA2 intracellular region. EphA2 promotes cancer malignancy through a poorly understood non-canonical form of signaling involving serine/threonine phosphorylation of the linker connecting its kinase and SAM domains. We show that accumulation of multiple linker negative charges, mimicking phosphorylation, induces cooperative changes in the EphA2 intracellular region from more closed to more extended conformations and perturbs the EphA2 juxtamembrane segment and kinase domain. In cells, linker negative charges promote EphA2 oligomerization. We also identify multiple kinases catalyzing linker phosphorylation. Our findings suggest multiple effects of linker phosphorylation on EphA2 signaling and imply that coordination of different kinases is necessary to promote EphA2 non-canonical signaling. Nature Publishing Group UK 2021-12-02 /pmc/articles/PMC8639986/ /pubmed/34857764 http://dx.doi.org/10.1038/s41467-021-27343-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lechtenberg, Bernhard C. Gehring, Marina P. Light, Taylor P. Horne, Christopher R. Matsumoto, Mike W. Hristova, Kalina Pasquale, Elena B. Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker |
title | Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker |
title_full | Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker |
title_fullStr | Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker |
title_full_unstemmed | Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker |
title_short | Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker |
title_sort | regulation of the epha2 receptor intracellular region by phosphomimetic negative charges in the kinase-sam linker |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639986/ https://www.ncbi.nlm.nih.gov/pubmed/34857764 http://dx.doi.org/10.1038/s41467-021-27343-z |
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