Towards a molecular basis of ubiquitin signaling: A dual-scale simulation study of ubiquitin dimers.
Towards a molecular basis of ubiquitin signaling: A dual-scale simulation study of ubiquitin dimers.
复制标题
依靠泛素信号的分子基础：泛素二聚体的双尺度模拟研究。
DOI：
10.1371/journal.pcbi.1006589
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发表时间：
2018-11
影响因子：
4.3
通讯作者：
Peter C
中科院分区：
文献类型：
--
作者：
Berg A;Kukharenko O;Scheffner M;Peter C
泛素或泛素链对蛋白质的共价修饰是真核生物中最普遍的翻译后修饰之一。假设不同类型的泛素链选择性地向不同命运的修饰蛋白发出信号。为了支持这一假设，结构研究表明，八种可能的泛素二聚体采用不同的构象。然而，至少在某些情况下，这些结构不能充分解释选择性信号传导机制的分子基础。这表明，在泛素二聚体所采用的整个构象空间中，可用的结构仅代表少数不同的构象。在这里，不同分辨率的分子模拟可以补充结构信息。我们将所有八种可能的泛素二聚体的详尽的粗粒度和原子模拟与合适的降维技术和表征蛋白质-蛋白质界面和蛋白质偶联物构象景观的新方法相结合。我们发现，泛素二聚体在溶液中表现出典型的键类型依赖性质，如界面稳定性和亚基之间的接触特征，这可以直接与实验观察到的键特异性性质相关。通过泛素的共价附着对蛋白质进行翻译后修饰是一个关键的细胞过程，例如调节蛋白质的命运和循环。我们提出了一种结合多尺度模拟和先进分析方法来表征泛素-泛素偶联物状态的新方法。我们发现，键的位置影响了泛素二聚体的构象空间，决定了相关状态的数量和稳定性，亚基接触的特征以及暴露于可能的结合伙伴的表面的性质。
Covalent modification of proteins by ubiquitin or ubiquitin chains is one of the most prevalent post-translational modifications in eukaryotes. Different types of ubiquitin chains are assumed to selectively signal respectively modified proteins for different fates. In support of this hypothesis, structural studies have shown that the eight possible ubiquitin dimers adopt different conformations. However, at least in some cases, these structures cannot sufficiently explain the molecular basis of the selective signaling mechanisms. This indicates that the available structures represent only a few distinct conformations within the entire conformational space adopted by a ubiquitin dimer. Here, molecular simulations on different levels of resolution can complement the structural information. We have combined exhaustive coarse grained and atomistic simulations of all eight possible ubiquitin dimers with a suitable dimensionality reduction technique and a new method to characterize protein-protein interfaces and the conformational landscape of protein conjugates. We found that ubiquitin dimers exhibit characteristic linkage type-dependent properties in solution, such as interface stability and the character of contacts between the subunits, which can be directly correlated with experimentally observed linkage-specific properties. Post-translational modification of proteins by covalent attachment of ubiquitin is a key cellular process, regulating for example the fate and recycling of proteins. We present a new method to combine multiscale simulation with advanced analysis methods to characterize the states of ubiquitin-ubiquitin conjugates. We found that the linkage position affects the conformational space of ubiquitin dimers, determining the number and stability of relevant states, the character of subunit contacts and the nature of the surface exposed to possible binding partners.
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影响因子：
7.7
作者：
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通讯作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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Lys48 连接的双泛素开放状态的结构和生化研究。
DOI：
10.1016/j.bbamcr.2012.04.003
发表时间：
2012-11
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Lai MY;Zhang D;Laronde-Leblanc N;Fushman D
通讯作者：
Fushman D