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Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands
Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640019/ https://www.ncbi.nlm.nih.gov/pubmed/34857742 http://dx.doi.org/10.1038/s41467-021-26983-5 |
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author | Linossi, Edmond M. Li, Kunlun Veggiani, Gianluca Tan, Cyrus Dehkhoda, Farhad Hockings, Colin Calleja, Dale J. Keating, Narelle Feltham, Rebecca Brooks, Andrew J. Li, Shawn S. Sidhu, Sachdev S. Babon, Jeffrey J. Kershaw, Nadia J. Nicholson, Sandra E. |
author_facet | Linossi, Edmond M. Li, Kunlun Veggiani, Gianluca Tan, Cyrus Dehkhoda, Farhad Hockings, Colin Calleja, Dale J. Keating, Narelle Feltham, Rebecca Brooks, Andrew J. Li, Shawn S. Sidhu, Sachdev S. Babon, Jeffrey J. Kershaw, Nadia J. Nicholson, Sandra E. |
author_sort | Linossi, Edmond M. |
collection | PubMed |
description | Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling. |
format | Online Article Text |
id | pubmed-8640019 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86400192021-12-15 Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands Linossi, Edmond M. Li, Kunlun Veggiani, Gianluca Tan, Cyrus Dehkhoda, Farhad Hockings, Colin Calleja, Dale J. Keating, Narelle Feltham, Rebecca Brooks, Andrew J. Li, Shawn S. Sidhu, Sachdev S. Babon, Jeffrey J. Kershaw, Nadia J. Nicholson, Sandra E. Nat Commun Article Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling. Nature Publishing Group UK 2021-12-02 /pmc/articles/PMC8640019/ /pubmed/34857742 http://dx.doi.org/10.1038/s41467-021-26983-5 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 Linossi, Edmond M. Li, Kunlun Veggiani, Gianluca Tan, Cyrus Dehkhoda, Farhad Hockings, Colin Calleja, Dale J. Keating, Narelle Feltham, Rebecca Brooks, Andrew J. Li, Shawn S. Sidhu, Sachdev S. Babon, Jeffrey J. Kershaw, Nadia J. Nicholson, Sandra E. Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands |
title | Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands |
title_full | Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands |
title_fullStr | Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands |
title_full_unstemmed | Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands |
title_short | Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands |
title_sort | discovery of an exosite on the socs2-sh2 domain that enhances sh2 binding to phosphorylated ligands |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640019/ https://www.ncbi.nlm.nih.gov/pubmed/34857742 http://dx.doi.org/10.1038/s41467-021-26983-5 |
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