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Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity
TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA), originally identified as an adaptor protein of TRAF6, has recently been shown to be involved in innate immunity, induced by a pathogen-associated molecular pattern (PAMP). ADP-β-D-manno-heptose, a newly identified PAMP, binds t...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083832/ https://www.ncbi.nlm.nih.gov/pubmed/32198460 http://dx.doi.org/10.1038/s41598-020-61972-6 |
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author | Nakamura, Teruya Hashikawa, Chie Okabe, Kohtaro Yokote, Yuya Chirifu, Mami Toma-Fukai, Sachiko Nakamura, Narushi Matsuo, Mihoko Kamikariya, Miho Okamoto, Yoshinari Gohda, Jin Akiyama, Taishin Semba, Kentaro Ikemizu, Shinji Otsuka, Masami Inoue, Jun-ichiro Yamagata, Yuriko |
author_facet | Nakamura, Teruya Hashikawa, Chie Okabe, Kohtaro Yokote, Yuya Chirifu, Mami Toma-Fukai, Sachiko Nakamura, Narushi Matsuo, Mihoko Kamikariya, Miho Okamoto, Yoshinari Gohda, Jin Akiyama, Taishin Semba, Kentaro Ikemizu, Shinji Otsuka, Masami Inoue, Jun-ichiro Yamagata, Yuriko |
author_sort | Nakamura, Teruya |
collection | PubMed |
description | TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA), originally identified as an adaptor protein of TRAF6, has recently been shown to be involved in innate immunity, induced by a pathogen-associated molecular pattern (PAMP). ADP-β-D-manno-heptose, a newly identified PAMP, binds to alpha-kinase 1 (ALPK1) and activates its kinase activity to phosphorylate TIFA. Phosphorylation triggers TIFA oligomerisation and formation of a subsequent TIFA–TRAF6 oligomeric complex for ubiquitination of TRAF6, eventually leading to NF-κB activation. However, the structural basis of TIFA-dependent TRAF6 signalling, especially oligomer formation of the TIFA–TRAF6 complex remains unknown. In the present study, we determined the crystal structures of mouse TIFA and two TIFA mutants—Thr9 mutated to either Asp or Glu to mimic the phosphorylation state—to obtain the structural information for oligomer formation of the TIFA–TRAF6 complex. Crystal structures show the dimer formation of mouse TIFA to be similar to that of human TIFA, which was previously reported. This dimeric structure is consistent with the solution structure obtained from small angle X-ray scattering analysis. In addition to the structural analysis, we examined the molecular assembly of TIFA and the TIFA–TRAF6 complex by size-exclusion chromatography, and suggested a model for the TIFA–TRAF6 signalling complex. |
format | Online Article Text |
id | pubmed-7083832 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70838322020-03-26 Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity Nakamura, Teruya Hashikawa, Chie Okabe, Kohtaro Yokote, Yuya Chirifu, Mami Toma-Fukai, Sachiko Nakamura, Narushi Matsuo, Mihoko Kamikariya, Miho Okamoto, Yoshinari Gohda, Jin Akiyama, Taishin Semba, Kentaro Ikemizu, Shinji Otsuka, Masami Inoue, Jun-ichiro Yamagata, Yuriko Sci Rep Article TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA), originally identified as an adaptor protein of TRAF6, has recently been shown to be involved in innate immunity, induced by a pathogen-associated molecular pattern (PAMP). ADP-β-D-manno-heptose, a newly identified PAMP, binds to alpha-kinase 1 (ALPK1) and activates its kinase activity to phosphorylate TIFA. Phosphorylation triggers TIFA oligomerisation and formation of a subsequent TIFA–TRAF6 oligomeric complex for ubiquitination of TRAF6, eventually leading to NF-κB activation. However, the structural basis of TIFA-dependent TRAF6 signalling, especially oligomer formation of the TIFA–TRAF6 complex remains unknown. In the present study, we determined the crystal structures of mouse TIFA and two TIFA mutants—Thr9 mutated to either Asp or Glu to mimic the phosphorylation state—to obtain the structural information for oligomer formation of the TIFA–TRAF6 complex. Crystal structures show the dimer formation of mouse TIFA to be similar to that of human TIFA, which was previously reported. This dimeric structure is consistent with the solution structure obtained from small angle X-ray scattering analysis. In addition to the structural analysis, we examined the molecular assembly of TIFA and the TIFA–TRAF6 complex by size-exclusion chromatography, and suggested a model for the TIFA–TRAF6 signalling complex. Nature Publishing Group UK 2020-03-20 /pmc/articles/PMC7083832/ /pubmed/32198460 http://dx.doi.org/10.1038/s41598-020-61972-6 Text en © The Author(s) 2020 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/. |
spellingShingle | Article Nakamura, Teruya Hashikawa, Chie Okabe, Kohtaro Yokote, Yuya Chirifu, Mami Toma-Fukai, Sachiko Nakamura, Narushi Matsuo, Mihoko Kamikariya, Miho Okamoto, Yoshinari Gohda, Jin Akiyama, Taishin Semba, Kentaro Ikemizu, Shinji Otsuka, Masami Inoue, Jun-ichiro Yamagata, Yuriko Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity |
title | Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity |
title_full | Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity |
title_fullStr | Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity |
title_full_unstemmed | Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity |
title_short | Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity |
title_sort | structural analysis of tifa: insight into tifa-dependent signal transduction in innate immunity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083832/ https://www.ncbi.nlm.nih.gov/pubmed/32198460 http://dx.doi.org/10.1038/s41598-020-61972-6 |
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