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: | , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2018
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/bfe5b5c5f6374e74b7c5837507173ede |
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| Sumario: | 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. |
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