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Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8)
Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin α(V)β(8) activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 pre...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411592/ https://www.ncbi.nlm.nih.gov/pubmed/36008481 http://dx.doi.org/10.1038/s41467-022-32655-9 |
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author | Duan, Zelin Lin, Xuezhen Wang, Lixia Zhen, Qiuxin Jiang, Yuefeng Chen, Chuxin Yang, Jing Lee, Chia-Hsueh Qin, Yan Li, Ying Zhao, Bo Wang, Jianchuan Zhang, Zhe |
author_facet | Duan, Zelin Lin, Xuezhen Wang, Lixia Zhen, Qiuxin Jiang, Yuefeng Chen, Chuxin Yang, Jing Lee, Chia-Hsueh Qin, Yan Li, Ying Zhao, Bo Wang, Jianchuan Zhang, Zhe |
author_sort | Duan, Zelin |
collection | PubMed |
description | Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin α(V)β(8) activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin α(V)β(8)/L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin α(V)β(8) and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β(8) determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin α(V)β(8). |
format | Online Article Text |
id | pubmed-9411592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94115922022-08-27 Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) Duan, Zelin Lin, Xuezhen Wang, Lixia Zhen, Qiuxin Jiang, Yuefeng Chen, Chuxin Yang, Jing Lee, Chia-Hsueh Qin, Yan Li, Ying Zhao, Bo Wang, Jianchuan Zhang, Zhe Nat Commun Article Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin α(V)β(8) activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin α(V)β(8)/L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin α(V)β(8) and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β(8) determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin α(V)β(8). Nature Publishing Group UK 2022-08-25 /pmc/articles/PMC9411592/ /pubmed/36008481 http://dx.doi.org/10.1038/s41467-022-32655-9 Text en © The Author(s) 2022 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 Duan, Zelin Lin, Xuezhen Wang, Lixia Zhen, Qiuxin Jiang, Yuefeng Chen, Chuxin Yang, Jing Lee, Chia-Hsueh Qin, Yan Li, Ying Zhao, Bo Wang, Jianchuan Zhang, Zhe Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) |
title | Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) |
title_full | Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) |
title_fullStr | Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) |
title_full_unstemmed | Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) |
title_short | Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8) |
title_sort | specificity of tgf-β1 signal designated by lrrc33 and integrin α(v)β(8) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411592/ https://www.ncbi.nlm.nih.gov/pubmed/36008481 http://dx.doi.org/10.1038/s41467-022-32655-9 |
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