Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor
Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor
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DOI：
10.1016/j.molcel.2006.04.024
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发表时间：
2006-06-09
期刊：
影响因子：
16
通讯作者：
Ish-Horowicz, David
中科院分区：
文献类型：
--
作者：
Jennings, Barbara H.;Pickles, Laura M.;Ish-Horowicz, David
grocho (Gro)/TLE/Grg家族共阻遏因子在许多信号通路中起作用（包括Notch和Wnt）。Gro/TLE蛋白通过结合不同的短肽序列识别广泛的转录抑制因子，包括c端WRPW/Y基序（Hairy/Hes/Runx）和内部eh1基序（FxIxxIL; Engrailed/Goosecoid/Pax/Nkx）。在这里，我们在果蝇Gro中发现了几个错义突变，这些突变在体外和体内都证明了肽与WD (WD40) β螺旋桨结构域的中心孔结合。我们在分子水平上定义了这些相互作用，即人类TLE1与WRPW或eh1肽结合的WD结构域的晶体结构。这两种不同的肽基序采用明显不同的结合构象，但在β螺旋桨的中央孔中占据重叠的位点。我们的结构和功能分析解释了WRPW基序的刚性保守性、eh1基序的序列灵活性以及Gro在体内识别阻遏物的其他方面。
The Groucho (Gro)/TLE/Grg family of corepressors operates in many signaling pathways (including Notch and Wnt). Gro/TLE proteins recognize a wide range of transcriptional repressors by binding to divergent short peptide sequences, including a C-terminal WRPW/Y motif (Hairy/Hes/Runx) and internal eh1 motifs (FxIxxIL; Engrailed/Goosecoid/Pax/Nkx). Here, we identify several missense mutations in Drosophila Gro, which demonstrate peptide binding to the central pore of the WD (WD40) beta propeller domain in vitro and in vivo. We define these interactions at the molecular level with crystal structures of the WD domain of human TLE1 bound to either WRPW or eh1 peptides. The two distinct peptide motifs adopt markedly different bound conformations but occupy overlapping sites across the central pore of the beta propeller. Our structural and functional analysis explains the rigid conservation of the WRPW motif, the sequence flexibility of eh1 motifs, and other aspects of repressor recognition by Gro in vivo.