The 'dark matter' of ubiquitin-mediated processes: opportunities and challenges in the identification of ubiquitin-binding domains.
The 'dark matter' of ubiquitin-mediated processes: opportunities and challenges in the identification of ubiquitin-binding domains.
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DOI：
10.1042/bst20190869
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发表时间：
2019-12
影响因子：
3.9
通讯作者：
Elizabeth H Radley;J. Long;K. Gough;R. Layfield
中科院分区：
文献类型：
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作者：
Elizabeth H Radley;J. Long;K. Gough;R. Layfield
靶蛋白的泛素修饰用于定位、指导和指定多种细胞过程，其中许多是生物医学相关的。为了允许这种多样性，泛素修饰表现出显着的复杂性，由多聚泛素链长度，连接类型，每个目标的泛素链的数量，和泛素与其他小修饰剂的装饰的组合决定。然而，许多问题仍然是关于不同的泛素信号是如何特异性地识别和转导的泛素结合蛋白内的泛素结合结构域（UBD）的解码。这篇综述简要概述了我们目前对UBD多样性的了解，确定了发现它们的关键挑战，并考虑了最近的结构研究对UBD功能和识别日益复杂的影响。鉴于相对于不断扩大的多种多聚泛素修饰，功能特征的多聚泛素选择性UBD的数量相对较少，可能许多UBD被忽视，部分原因是目前用于预测其在蛋白质组中存在的方法的局限性。潜在的实验方法为UBD的发现被认为是基于网络的信息分析，下一代噬菌体展示，去泛素化酶抗性diubiquitin，邻近依赖性生物素化和泛素phototrap，包括可能的优点和局限性。这里讨论的概念工作，以确定新的UBD可能代表的“暗物质”的泛素系统。
Ubiquitin modifications of target proteins act to localise, direct and specify a diverse range of cellular processes, many of which are biomedically relevant. To allow this diversity, ubiquitin modifications exhibit remarkable complexity, determined by a combination of polyubiquitin chain length, linkage type, numbers of ubiquitin chains per target, and decoration of ubiquitin with other small modifiers. However, many questions remain about how different ubiquitin signals are specifically recognised and transduced by the decoding ubiquitin-binding domains (UBDs) within ubiquitin-binding proteins. This review briefly outlines our current knowledge surrounding the diversity of UBDs, identifies key challenges in their discovery and considers recent structural studies with implications for the increasing complexity of UBD function and identification. Given the comparatively low numbers of functionally characterised polyubiquitin-selective UBDs relative to the ever-expanding variety of polyubiquitin modifications, it is possible that many UBDs have been overlooked, in part due to limitations of current approaches used to predict their presence within the proteome. Potential experimental approaches for UBD discovery are considered; web-based informatic analyses, Next-Generation Phage Display, deubiquitinase-resistant diubiquitin, proximity-dependent biotinylation and Ubiquitin-Phototrap, including possible advantages and limitations. The concepts discussed here work towards identifying new UBDs which may represent the 'dark matter' of the ubiquitin system.