Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily

Abstract The TNFR1-associated death domain protein (TRADD) is an intracellular adaptor protein involved in various signaling pathways, such as antiapoptosis. Its C-terminal death domain (DD) is responsible for binding other DD-containing proteins including the p75 neurotrophin receptor (p75NTR). Her...

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Autores principales:	Ning Zhang, Wensu Yuan, Jing-Song Fan, Zhi Lin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/88752427b999495aaeb3087ce1d16f6e
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spelling	oai:doaj.org-article:88752427b999495aaeb3087ce1d16f6e2021-12-02T12:32:45ZStructure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily10.1038/s41598-017-07348-92045-2322https://doaj.org/article/88752427b999495aaeb3087ce1d16f6e2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07348-9https://doaj.org/toc/2045-2322Abstract The TNFR1-associated death domain protein (TRADD) is an intracellular adaptor protein involved in various signaling pathways, such as antiapoptosis. Its C-terminal death domain (DD) is responsible for binding other DD-containing proteins including the p75 neurotrophin receptor (p75NTR). Here we present a solution structure of TRADD DD derived from high-resolution NMR spectroscopy. The TRADD DD comprises two super-secondary structures, an all-helix Greek key motif and a β-hairpin motif flanked by two α helices, which make it unique among all known DD structures. The β-hairpin motif is essential for TRADD DD to fold into a functional globular domain. The highly-charged surface suggests a critical role of electrostatic interactions in TRADD DD-mediated signaling. This novel structure represents a new class within the DD superfamily and provides a structural basis for studying homotypic DD interactions. NMR titration revealed a direct weak interaction between TRADD DD and p75NTR DD monomers. A binding site next to the p75NTR DD homodimerization interface indicates that TRADD DD recruitment to p75NTR requires separation of the p75NTR DD homodimer, explaining the mechanism of NGF-dependent activation of p75NTR-TRADD-mediated antiapoptotic pathway in breast cancer cell.Ning ZhangWensu YuanJing-Song FanZhi LinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ning Zhang Wensu Yuan Jing-Song Fan Zhi Lin Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily
description	Abstract The TNFR1-associated death domain protein (TRADD) is an intracellular adaptor protein involved in various signaling pathways, such as antiapoptosis. Its C-terminal death domain (DD) is responsible for binding other DD-containing proteins including the p75 neurotrophin receptor (p75NTR). Here we present a solution structure of TRADD DD derived from high-resolution NMR spectroscopy. The TRADD DD comprises two super-secondary structures, an all-helix Greek key motif and a β-hairpin motif flanked by two α helices, which make it unique among all known DD structures. The β-hairpin motif is essential for TRADD DD to fold into a functional globular domain. The highly-charged surface suggests a critical role of electrostatic interactions in TRADD DD-mediated signaling. This novel structure represents a new class within the DD superfamily and provides a structural basis for studying homotypic DD interactions. NMR titration revealed a direct weak interaction between TRADD DD and p75NTR DD monomers. A binding site next to the p75NTR DD homodimerization interface indicates that TRADD DD recruitment to p75NTR requires separation of the p75NTR DD homodimer, explaining the mechanism of NGF-dependent activation of p75NTR-TRADD-mediated antiapoptotic pathway in breast cancer cell.
format	article
author	Ning Zhang Wensu Yuan Jing-Song Fan Zhi Lin
author_facet	Ning Zhang Wensu Yuan Jing-Song Fan Zhi Lin
author_sort	Ning Zhang
title	Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily
title_short	Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily
title_full	Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily
title_fullStr	Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily
title_full_unstemmed	Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily
title_sort	structure of the c-terminal domain of tradd reveals a novel fold in the death domain superfamily
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/88752427b999495aaeb3087ce1d16f6e
work_keys_str_mv	AT ningzhang structureofthecterminaldomainoftraddrevealsanovelfoldinthedeathdomainsuperfamily AT wensuyuan structureofthecterminaldomainoftraddrevealsanovelfoldinthedeathdomainsuperfamily AT jingsongfan structureofthecterminaldomainoftraddrevealsanovelfoldinthedeathdomainsuperfamily AT zhilin structureofthecterminaldomainoftraddrevealsanovelfoldinthedeathdomainsuperfamily
_version_	1718393990612516864

Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily

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