Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex

Abstract Poly-ubiquitin (poly-Ub) is involved in various cellular processes through the linkage-specific recognition of Ub-binding domains (UBD). In this study, using molecular dynamics (MD) simulation together with an enhanced sampling method, we demonstrated that K63-linked di-Ub recognizes the NZ...

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Autores principales:	Kei Moritsugu, Hafumi Nishi, Keiichi Inariyama, Masanori Kobayashi, Akinori Kidera
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	TAK1-binding Protein (TAB2) Linkage Specificity Dynamic Recognition Ub-binding Domains (UBD) Transforming Growth Factor Β-activated Kinase (TAK1) Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bfe5b5c5f6374e74b7c5837507173ede
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spelling	oai:doaj.org-article:bfe5b5c5f6374e74b7c5837507173ede2021-12-02T15:08:52ZDynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex10.1038/s41598-018-34605-22045-2322https://doaj.org/article/bfe5b5c5f6374e74b7c5837507173ede2018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34605-2https://doaj.org/toc/2045-2322Abstract Poly-ubiquitin (poly-Ub) is involved in various cellular processes through the linkage-specific recognition of Ub-binding domains (UBD). In this study, using molecular dynamics (MD) simulation together with an enhanced sampling method, we demonstrated that K63-linked di-Ub recognizes the NZF domain of TAB2, a zinc finger UBD, in an ensemble of highly dynamic structures that form from the weak interactions between UBD and the flexible linker connecting the two Ubs. However, the K63 di-Ub/TAB2 NZF complex showed a much more compact and stable ensemble than the non-native complexes, linear di-Ub/TAB2 NZF and K33 di-Ub/TAB2 NZF, that were modeled from linear di-Ub/HOIL-1L NZF and K33 di-Ub/TRABID NZF1, respectively. We further demonstrated the importance of the length and position of the Ub-Ub linker in the results of MD simulations of K63 di-Ub/TAB2 NZF by changing the Ub linkage from the native K63 to four different non-native linkages, linear, K6, K11, and K48, while maintaining inter-molecular contacts in the native complex. No systems with non-native linkage maintained the native binding configuration. These simulation results provide an atomistic picture of the linkage specific recognition of poly-Ubs leading to the biological functions such as cellular colocalization of various component proteins in the signal transduction pathways.Kei MoritsuguHafumi NishiKeiichi InariyamaMasanori KobayashiAkinori KideraNature PortfolioarticleTAK1-binding Protein (TAB2)Linkage SpecificityDynamic RecognitionUb-binding Domains (UBD)Transforming Growth Factor Β-activated Kinase (TAK1)MedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	TAK1-binding Protein (TAB2) Linkage Specificity Dynamic Recognition Ub-binding Domains (UBD) Transforming Growth Factor Β-activated Kinase (TAK1) Medicine R Science Q
spellingShingle	TAK1-binding Protein (TAB2) Linkage Specificity Dynamic Recognition Ub-binding Domains (UBD) Transforming Growth Factor Β-activated Kinase (TAK1) Medicine R Science Q Kei Moritsugu Hafumi Nishi Keiichi Inariyama Masanori Kobayashi Akinori Kidera Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
description	Abstract Poly-ubiquitin (poly-Ub) is involved in various cellular processes through the linkage-specific recognition of Ub-binding domains (UBD). In this study, using molecular dynamics (MD) simulation together with an enhanced sampling method, we demonstrated that K63-linked di-Ub recognizes the NZF domain of TAB2, a zinc finger UBD, in an ensemble of highly dynamic structures that form from the weak interactions between UBD and the flexible linker connecting the two Ubs. However, the K63 di-Ub/TAB2 NZF complex showed a much more compact and stable ensemble than the non-native complexes, linear di-Ub/TAB2 NZF and K33 di-Ub/TAB2 NZF, that were modeled from linear di-Ub/HOIL-1L NZF and K33 di-Ub/TRABID NZF1, respectively. We further demonstrated the importance of the length and position of the Ub-Ub linker in the results of MD simulations of K63 di-Ub/TAB2 NZF by changing the Ub linkage from the native K63 to four different non-native linkages, linear, K6, K11, and K48, while maintaining inter-molecular contacts in the native complex. No systems with non-native linkage maintained the native binding configuration. These simulation results provide an atomistic picture of the linkage specific recognition of poly-Ubs leading to the biological functions such as cellular colocalization of various component proteins in the signal transduction pathways.
format	article
author	Kei Moritsugu Hafumi Nishi Keiichi Inariyama Masanori Kobayashi Akinori Kidera
author_facet	Kei Moritsugu Hafumi Nishi Keiichi Inariyama Masanori Kobayashi Akinori Kidera
author_sort	Kei Moritsugu
title	Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
title_short	Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
title_full	Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
title_fullStr	Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
title_full_unstemmed	Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
title_sort	dynamic recognition and linkage specificity in k63 di-ubiquitin and tab2 nzf domain complex
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/bfe5b5c5f6374e74b7c5837507173ede
work_keys_str_mv	AT keimoritsugu dynamicrecognitionandlinkagespecificityink63diubiquitinandtab2nzfdomaincomplex AT hafuminishi dynamicrecognitionandlinkagespecificityink63diubiquitinandtab2nzfdomaincomplex AT keiichiinariyama dynamicrecognitionandlinkagespecificityink63diubiquitinandtab2nzfdomaincomplex AT masanorikobayashi dynamicrecognitionandlinkagespecificityink63diubiquitinandtab2nzfdomaincomplex AT akinorikidera dynamicrecognitionandlinkagespecificityink63diubiquitinandtab2nzfdomaincomplex
_version_	1718388024426889216

Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex

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