Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation.
Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation.
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DOI：
10.1107/s0907444913028473
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Toftgård R
中科院分区：
文献类型：
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作者：
Cherry AL;Finta C;Karlström M;Jin Q;Schwend T;Astorga-Wells J;Zubarev RA;Del Campo M;Criswell AR;de Sanctis D;Jovine L;Toftgård R
晶体和小角X射线散射结构的全长人SUFU单独和复杂的保守SYGHL基序从GLI转录因子显示主要的构象变化与结合，揭示了一个内在的无序区域的途径激活至关重要。Hedgehog信号传导在后生动物发育、细胞增殖和分化的控制中起着重要作用，正如其失调与许多人类肿瘤的发展相关的事实所强调的那样。SUFU是哺乳动物Hedgehog信号传导的重要细胞内负调节因子，通过结合和调节GLI转录因子的活性发挥作用。尽管其核心的重要性，很少有人知道SUFU的调节和SUFU-GLI相互作用的性质。在这里，晶体和小角X射线散射结构的全长人SUFU及其复杂的关键SYGHL基序保守在所有GLI的报告。它表明，GLI结合与SUFU的主要构象变化，包括一个内在的无序环，也是至关重要的途径激活。这些发现揭示了SUFU-GLI界面的结构，并提出了Hedgehog信号传导中重要调控步骤的机制，为开发新的通路调节剂和治疗方法提供了可能性。
Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.