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Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L
SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders inc...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795524/ https://www.ncbi.nlm.nih.gov/pubmed/35046037 http://dx.doi.org/10.1073/pnas.2116550119 |
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author | Peng, Shuxia Meng, Xiangzhi Zhang, Fushun Pathak, Prabhat Kumar Chaturvedi, Juhi Coronado, Jaime Morales, Marisol Mao, Yuanhui Qian, Shu-Bing Deng, Junpeng Xiang, Yan |
author_facet | Peng, Shuxia Meng, Xiangzhi Zhang, Fushun Pathak, Prabhat Kumar Chaturvedi, Juhi Coronado, Jaime Morales, Marisol Mao, Yuanhui Qian, Shu-Bing Deng, Junpeng Xiang, Yan |
author_sort | Peng, Shuxia |
collection | PubMed |
description | SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases. |
format | Online Article Text |
id | pubmed-8795524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-87955242022-07-19 Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L Peng, Shuxia Meng, Xiangzhi Zhang, Fushun Pathak, Prabhat Kumar Chaturvedi, Juhi Coronado, Jaime Morales, Marisol Mao, Yuanhui Qian, Shu-Bing Deng, Junpeng Xiang, Yan Proc Natl Acad Sci U S A Biological Sciences SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases. National Academy of Sciences 2022-01-19 2022-01-25 /pmc/articles/PMC8795524/ /pubmed/35046037 http://dx.doi.org/10.1073/pnas.2116550119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Peng, Shuxia Meng, Xiangzhi Zhang, Fushun Pathak, Prabhat Kumar Chaturvedi, Juhi Coronado, Jaime Morales, Marisol Mao, Yuanhui Qian, Shu-Bing Deng, Junpeng Xiang, Yan Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L |
title | Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L |
title_full | Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L |
title_fullStr | Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L |
title_full_unstemmed | Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L |
title_short | Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L |
title_sort | structure and function of an effector domain in antiviral factors and tumor suppressors samd9 and samd9l |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795524/ https://www.ncbi.nlm.nih.gov/pubmed/35046037 http://dx.doi.org/10.1073/pnas.2116550119 |
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