SCFFbx4 对 TRF1 的选择性泛素化的结构基础。
Structural basis of selective ubiquitination of TRF1 by SCFFbx4.
机构信息
Howard Hughes Medical Institute, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
出版信息
Dev Cell. 2010 Feb 16;18(2):214-25. doi: 10.1016/j.devcel.2010.01.007.
TRF1 is a critical regulator of telomere length. As such, TRF1 levels are regulated by ubiquitin-dependent proteolysis via an SCF E3 ligase where Fbx4 contributes to substrate specification. Here, we report the crystal structure of the Fbx4-TRF1 complex at 2.4 A resolution. Fbx4 contains an unusual substrate-binding domain that adopts a small GTPase fold. Strikingly, this atypical GTPase domain of Fbx4 binds to a globular domain of TRF1 through an intermolecular beta sheet, instead of recognizing short peptides/degrons as often seen in other F-box protein-substrate complexes. Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination. Furthermore, the data demonstrate that recognition of TRF1 by SCF(Fbx4) is regulated by another telomere protein, TIN2. Our results reveal an atypical small GTPase domain within Fbx4 as a substrate-binding motif for SCF(Fbx4) and uncover a mechanism for selective ubiquitination and degradation of TRF1 in telomere homeostasis control.
TRF1 是端粒长度的关键调节因子。因此，TRF1 水平通过依赖泛素的蛋白酶体途径进行调节，其中 SCF E3 连接酶中的 Fbx4 有助于底物特异性。在这里，我们报告了 Fbx4-TRF1 复合物在 2.4 A 分辨率下的晶体结构。Fbx4 包含一个不寻常的底物结合结构域，采用小 GTPase 折叠。引人注目的是，Fbx4 的这种非典型 GTPase 结构域通过分子间 β 片层与 TRF1 的球状结构域结合，而不是像其他 F-box 蛋白-底物复合物中常见的那样识别短肽/降解基序。重要的是，该界面的突变会消除 Fbx4 依赖的 TRF1 结合和泛素化。此外，该数据表明，SCF(Fbx4)对 TRF1 的识别受另一个端粒蛋白 TIN2 调控。我们的结果揭示了 Fbx4 内的一个非典型小 GTPase 结构域作为 SCF(Fbx4)的底物结合基序，并揭示了在端粒稳态控制中选择性泛素化和降解 TRF1 的机制。
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