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TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2
The fully human monoclonal antibody KMTR2 acts as a strong direct agonist for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), which is capable of inducing apoptotic cell death without cross-linking. To investigate the mechanism of direct agonistic activity indu...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682084/ https://www.ncbi.nlm.nih.gov/pubmed/26672965 http://dx.doi.org/10.1038/srep17936 |
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author | Tamada, Taro Shinmi, Daisuke Ikeda, Masahiro Yonezawa, Yasushi Kataoka, Shiro Kuroki, Ryota Mori, Eiji Motoki, Kazuhiro |
author_facet | Tamada, Taro Shinmi, Daisuke Ikeda, Masahiro Yonezawa, Yasushi Kataoka, Shiro Kuroki, Ryota Mori, Eiji Motoki, Kazuhiro |
author_sort | Tamada, Taro |
collection | PubMed |
description | The fully human monoclonal antibody KMTR2 acts as a strong direct agonist for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), which is capable of inducing apoptotic cell death without cross-linking. To investigate the mechanism of direct agonistic activity induced by KMTR2, the crystal structure of the extracellular region of TRAIL-R2 and a Fab fragment derived from KMTR2 (KMTR2-Fab) was determined to 2.1 Å resolution. Two KMTR2-Fabs assembled with the complementarity-determining region 2 of the light chain via two-fold crystallographic symmetry, suggesting that the KMTR2-Fab assembly tended to enhance TRAIL-R2 oligomerization. A single mutation at Asn53 to Arg located at the two-fold interface in the KMTR2 resulted in a loss of its apoptotic activity, although it retained its antigen-binding activity. These results indicate that the strong agonistic activity, such as apoptotic signaling and tumor regression, induced by KMTR2 is attributed to TRAIL-R2 superoligomerization induced by the interdimerization of KMTR2. |
format | Online Article Text |
id | pubmed-4682084 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46820842015-12-18 TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 Tamada, Taro Shinmi, Daisuke Ikeda, Masahiro Yonezawa, Yasushi Kataoka, Shiro Kuroki, Ryota Mori, Eiji Motoki, Kazuhiro Sci Rep Article The fully human monoclonal antibody KMTR2 acts as a strong direct agonist for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), which is capable of inducing apoptotic cell death without cross-linking. To investigate the mechanism of direct agonistic activity induced by KMTR2, the crystal structure of the extracellular region of TRAIL-R2 and a Fab fragment derived from KMTR2 (KMTR2-Fab) was determined to 2.1 Å resolution. Two KMTR2-Fabs assembled with the complementarity-determining region 2 of the light chain via two-fold crystallographic symmetry, suggesting that the KMTR2-Fab assembly tended to enhance TRAIL-R2 oligomerization. A single mutation at Asn53 to Arg located at the two-fold interface in the KMTR2 resulted in a loss of its apoptotic activity, although it retained its antigen-binding activity. These results indicate that the strong agonistic activity, such as apoptotic signaling and tumor regression, induced by KMTR2 is attributed to TRAIL-R2 superoligomerization induced by the interdimerization of KMTR2. Nature Publishing Group 2015-12-17 /pmc/articles/PMC4682084/ /pubmed/26672965 http://dx.doi.org/10.1038/srep17936 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Tamada, Taro Shinmi, Daisuke Ikeda, Masahiro Yonezawa, Yasushi Kataoka, Shiro Kuroki, Ryota Mori, Eiji Motoki, Kazuhiro TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 |
title | TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 |
title_full | TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 |
title_fullStr | TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 |
title_full_unstemmed | TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 |
title_short | TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2 |
title_sort | trail-r2 superoligomerization induced by human monoclonal agonistic antibody kmtr2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682084/ https://www.ncbi.nlm.nih.gov/pubmed/26672965 http://dx.doi.org/10.1038/srep17936 |
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