Exploring the linkage dependence of polyubiquitin conformations using molecular modeling.
Exploring the linkage dependence of polyubiquitin conformations using molecular modeling.
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DOI：
10.1016/j.jmb.2009.10.039
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发表时间：
2010-01-29
影响因子：
5.6
通讯作者：
Walker O
中科院分区：
文献类型：
--
作者：
Fushman D;Walker O
通过共价连接小蛋白泛素或泛素分子的聚合链（称为多聚泛素）对蛋白质进行翻译后修饰涉及控制真核细胞中的多种过程。如何识别不同的多聚泛素信号的问题是理解各种类型的多聚泛素化的特异性的核心。在聚泛素中，单体通过一个泛素的C-末端甘氨酸和另一个泛素的赖氨酸之间的异肽键彼此连接。多聚泛素化的功能结果取决于参与链形成的特定赖氨酸，并且似乎依赖于多聚泛素的连接依赖性构象。因此，K48连接的链，蛋白酶体降解的通用信号，在生理条件下采用封闭构象，其中功能上重要的残基L 8，I44和V70被隔离在两个相邻的泛素单体之间的界面。相比之下，K63连接的链，作为一个非蛋白水解，调节信号，采取了扩展的构象，缺乏疏水性的泛素间的接触。关于所谓的“非典型”链的功能作用知之甚少，这些链通过K6，K11，K27，K29，K33或头-尾连接;除了头-尾连接的双泛素的晶体结构外，没有关于这些链的结构信息。在这项研究中，我们使用分子建模来检查是否任何非典型的链可以采取类似于K48连接的多聚泛素的封闭构象。我们的研究结果表明，八个可能的双泛素链可以分为两组：K6-，K11-，K27-，和K48-连接的链被预测形成一个封闭的构象，而通过K29，K33，K63，或头到尾连接的链由于空间位阻而不能形成这样的接触。这些预测被K48-、K63-和头-尾连接链的已知结构所验证。我们的研究还预测了通过K6，K11，3和K27连接的双泛素的结构模型。这些研究结果的联系选择性识别的非典型的多聚泛素信号的各种受体的影响进行了讨论。
Post-translational modification of proteins by covalent attachment of a small protein ubiquitin or a polymeric chain of ubiquitin molecules (called polyubiquitin) is involved in controlling a vast variety of processes in eukaryotic cells. The question of how different polyubiquitin signals are recognized is central to understanding the specificity of various types of polyubiquitination. In polyubiquitin, the monomers are linked to each other via an isopeptide bond between the C-terminal glycine of one ubiquitin and a lysine of the other. The functional outcome of polyubiquitination depends on the particular lysine involved in the chain formation and appears to rely on linkage-dependent conformation of polyubiquitin. Thus, K48-linked chains, a universal signal for proteasomal degradation, under physiological conditions adopt a closed conformation where functionally important residues L8, I44, and V70 are sequestered at the interface between the two adjacent ubiquitin monomers. By contrast, K63-linked chains, which act as a non-proteolytic, regulatory signal, adopt an extended conformation that lacks the hydrophobic inter-ubiquitin contact. Little is known about functional roles of the so-called “non-canonical” chains, linked via K6, K11, K27, K29, K33, or head-to-tail; and no structural information on these chains is available, except for the crystal structure of the head-to-tail linked diubiquitin. In this study, we use molecular modeling to examine whether any of the non-canonical chains can adopt a closed conformation similar to that in K48-linked polyubiquitin. Our results show that the eight possible di-ubiquitin chains can be divided into two groups: K6-, K11-, K27-, and K48-linked chains are predicted to form a closed conformation, whereas chains linked via K29, K33, K63, or head-to-tail are unable to form such a contact due to steric occlusion. These predictions are validated by the known structures of K48-, K63-, and head-to-tail linked chains. Our study also predicts structural models for di-ubiquitins linked via K6, K11, 3 and K27. Implications of these findings for linkage-selective recognition of the non-canonical polyubiquitin signals by various receptors are discussed.
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5.6
作者：
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通讯作者：
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