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Suppressor of Fused Regulates Gli Activity through a Dual Binding Mechanism

机译：融合抑制因子通过双重结合机制调节Gli活性。

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The Hedgehog pathway drives proliferation and differentiation by activating the Gli/Ci family of zinc finger transcription factors. Gli/Ci proteins form Hedgehog signaling complexes with other signaling components, including the kinesin-like protein Costal-2, the serine-threonine kinase Fused, and Suppressor of Fused [Su(fu)]. In these complexes Gli/Ci proteins are regulated by cytoplasmic sequestration, phosphorylation, and proteolysis. Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1. Furthermore, we have solved the crystal structure of the amino-terminal domain of human Su(fu)27-268 at 2.65 ? resolution. This domain forms a concave pocket with a prominent acidic patch. Mutation at Asp159 in the acidic patch disrupts Gli1 tethering and repression while not strongly disrupting binding, indicating that the amino-terminal domain of Su(fu) likely impacts Gli binding through a mechanism distinct from that for tethering and repression. These studies provide a structural basis for understanding the function of Su(fu).
机译：刺猬通路通过激活锌指转录因子的Gli / Ci家族来驱动增殖和分化。 Gli / Ci蛋白与其他信号转导成分（包括驱动蛋白样蛋白Costal-2，融合的丝氨酸-苏氨酸激酶和融合的[Su（fu）]抑制剂）形成了Hedgehog信号复合物。在这些复合物中，Gli / Ci蛋白受细胞质螯合，磷酸化和蛋白水解作用的调节。在这里我们表征了Gli调节所需的Su（fu）的结构和功能决定因素，并显示Su（fu）包含至少两个不同的域：结合至Gli蛋白的氨基末端所需的高度保守的羧基末端区域一个独特的氨基末端结构域，与Gli1的羧基末端尾部结合。虽然每个域都能够独立地绑定到不同的Gli1区，但是Su（fu）和Gli1在两个位点之间的相互作用对于胞质束缚和抑制Gli1是必需的。此外，我们已经解决了人Su（fu） 27-268 在2.65？处的氨基末端结构域的晶体结构。解析度。该畴形成具有突出的酸性斑块的凹形袋。酸性贴片中Asp 159 处的突变可破坏Gli1束缚和阻遏，而不会强烈破坏结合，表明Su（fu）的氨基末端结构域可能通过不同于束缚的机制影响Gli结合和镇压。这些研究为理解Su（fu）的功能提供了结构基础。

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