The N-terminal dimerization is required for TDP-43 splicing activity

Abstract TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and p...

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Autores principales:	Lei-Lei Jiang, Wei Xue, Jun-Ye Hong, Jun-Ting Zhang, Min-Jun Li, Shao-Ning Yu, Jian-Hua He, Hong-Yu Hu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ddf3e5d75a5b43d2a2fe776a5771ce0c
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spelling	oai:doaj.org-article:ddf3e5d75a5b43d2a2fe776a5771ce0c2021-12-02T12:32:58ZThe N-terminal dimerization is required for TDP-43 splicing activity10.1038/s41598-017-06263-32045-2322https://doaj.org/article/ddf3e5d75a5b43d2a2fe776a5771ce0c2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06263-3https://doaj.org/toc/2045-2322Abstract TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.Lei-Lei JiangWei XueJun-Ye HongJun-Ting ZhangMin-Jun LiShao-Ning YuJian-Hua HeHong-Yu HuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lei-Lei Jiang Wei Xue Jun-Ye Hong Jun-Ting Zhang Min-Jun Li Shao-Ning Yu Jian-Hua He Hong-Yu Hu The N-terminal dimerization is required for TDP-43 splicing activity
description	Abstract TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.
format	article
author	Lei-Lei Jiang Wei Xue Jun-Ye Hong Jun-Ting Zhang Min-Jun Li Shao-Ning Yu Jian-Hua He Hong-Yu Hu
author_facet	Lei-Lei Jiang Wei Xue Jun-Ye Hong Jun-Ting Zhang Min-Jun Li Shao-Ning Yu Jian-Hua He Hong-Yu Hu
author_sort	Lei-Lei Jiang
title	The N-terminal dimerization is required for TDP-43 splicing activity
title_short	The N-terminal dimerization is required for TDP-43 splicing activity
title_full	The N-terminal dimerization is required for TDP-43 splicing activity
title_fullStr	The N-terminal dimerization is required for TDP-43 splicing activity
title_full_unstemmed	The N-terminal dimerization is required for TDP-43 splicing activity
title_sort	n-terminal dimerization is required for tdp-43 splicing activity
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ddf3e5d75a5b43d2a2fe776a5771ce0c
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The N-terminal dimerization is required for TDP-43 splicing activity

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