Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503.
Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):839-44. doi: 10.1073/pnas.1322827111. Epub 2013 Dec 30.
Small heterodimer partner (SHP) is an orphan nuclear receptor that functions as a transcriptional repressor to regulate bile acid and cholesterol homeostasis. Although the precise mechanism whereby SHP represses transcription is not known, E1A-like inhibitor of differentiation (EID1) was isolated as a SHP-interacting protein and implicated in SHP repression. Here we present the crystal structure of SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site near the C-terminal helix H12, the EID1-binding site is located at the N terminus of the receptor, where EID1 mimics helix H1 of the nuclear receptor ligand-binding domain. The residues composing the SHP-EID1 interface are highly conserved. Their mutation diminishes SHP-EID1 interactions and affects SHP repressor activity. Together, these results provide important structural insights into SHP cofactor recruitment and repressor function and reveal a conserved protein interface that is likely to have broad implications for transcriptional repression by orphan nuclear receptors.
小异二聚体伴侣（SHP）是一种孤儿核受体，作为转录抑制剂调节胆汁酸和胆固醇的动态平衡。虽然 SHP 抑制转录的确切机制尚不清楚，但 E1A 样分化抑制剂（EID1）被分离为 SHP 相互作用蛋白，并暗示在 SHP 抑制中发挥作用。本文呈现了 SHP 与 EID1 复合物的晶体结构，揭示了 SHP 上一个意想不到的 EID1 结合位点。与经典的辅因子结合位点（靠近 C 端螺旋 H12）不同，EID1 结合位点位于受体的 N 端，EID1 模拟核受体配体结合域的螺旋 H1。构成 SHP-EID1 界面的残基高度保守。其突变会降低 SHP-EID1 相互作用，并影响 SHP 抑制活性。总之，这些结果为 SHP 辅助因子募集和抑制功能提供了重要的结构见解，并揭示了一个保守的蛋白质界面，可能对孤儿核受体的转录抑制具有广泛的影响。
