Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.
Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.
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DOI：
10.1038/nsmb.1607
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发表时间：
2009-07
影响因子：
16.8
通讯作者：
中科院分区：
文献类型：
--
作者：
刺猬（Hh）形态原在发育中发挥着重要作用，而Hh信号传导失调则导致疾病。多种细胞表面受体负责转导和/或调节Hh信号。其中，刺猬相互作用蛋白（HIP）是一个高度保守的，脊椎动物特异性，抑制剂Hh信号。我们已经解决了一系列的晶体结构的人HIP胞外域和沙漠Hh的隔离，以及声波和沙漠Hh-HIP复合物，有和没有钙。的相互作用的决定因素，证实了生物物理研究和诱变，揭示了新的和独特的功能Hh锌和钙结合位点的功能，出现常见的所有脊椎动物HHS。锌对Hh-HIP界面起关键作用，而钙阻止两种蛋白质之间的静电排斥，从而发挥主要的调节作用。几个金属结合位点的相互作用表明了调节Hh信号传导的可调机制。
Hedgehog (Hh) morphogens play fundamental roles in development whilst dysregulation of Hh signaling leads to disease. Multiple cell surface receptors are responsible for transducing and/or regulating Hh signals. Among these, the hedgehog-interacting protein (HIP) is a highly conserved, vertebrate-specific, inhibitor of Hh signaling. We have solved a series of crystal structures for the human HIP ectodomain and Desert Hh in isolation, as well as Sonic and Desert Hh-HIP complexes, with and without calcium. The interaction determinants, confirmed by biophysical studies and mutagenesis, reveal novel and distinct functions for Hh zinc- and calcium-binding sites; functions which appear common to all vertebrate Hhs. Zinc makes a key contribution to the Hh-HIP interface while calcium prevents electrostatic repulsion between the two proteins, thus playing a major modulatory role. This interplay of several metal-binding sites suggests a tuneable mechanism for regulation of Hh signaling.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
影响因子：
19
作者：
Beckett, Karen;Franch-Marro, Xavier;Vincent, Jean-Paul
通讯作者：
Vincent, Jean-Paul
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
2.9
作者：
Day, ES;Wen, DY;Baker, DP
通讯作者：
Baker, DP