The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.
The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.
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DOI：
10.1038/nature07358
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发表时间：
2008-10-16
期刊：
影响因子：
64.8
通讯作者：
Leahy, Daniel J.
中科院分区：
文献类型：
--
作者：
McLellan, Jason S.;Zheng, Xiaoyan;Hauk, Glenn;Ghirlando, Rodolfo;Beachy, Philip A.;Leahy, Daniel J.
Hedgehog（Hh）蛋白通过形成从离散表达位点发出的梯度并引起浓度依赖性细胞分化或增殖反应来指定后生动物胚胎中的组织模式。细胞对Hh的反应和Hh在组织中的运动都受到精确的调节，异常的Hh信号传导与人类出生缺陷和癌症有关。Hh信号传导由其N-末端结构域（HhN）介导，其作为多价脂蛋白颗粒的一部分被双重脂化和分泌。HhN信号的接收由响应细胞上的几种细胞表面蛋白调节，包括Patched（Ptc）、Smoothened（Smo）、Ihog/CDO和脊椎动物特异性蛋白Hip和Gas 1。果蝇Ihog及其脊椎动物同源物CDO和BOC含有多个免疫球蛋白（IG）和纤连蛋白III型（FNIII）重复序列，并且Ihog的第一个FNIII重复序列以肝素依赖性方式结合果蝇HhN。令人惊讶的是，下拉实验表明，哺乳动物音速刺猬（ShhN）结合的非正交FNIII重复的CDO。我们在这里报告的生化，生物物理和X-射线结构研究之间的复杂ShhN和第三FNIII重复CDO。我们表明，ShhN-CDO相互作用是完全不同的HhN-Ihog相互作用，需要钙，结合在一个以前未检测到的网站上ShhN。该位点在几乎所有Hh蛋白中是保守的，并且是介导ShhN与CDO、Ptc、Hip和Gas 1之间相互作用的热点。脊椎动物Hh蛋白的突变导致前脑无裂畸形和短趾畸形A1型映射到这个钙结合位点，并破坏与这些合作伙伴的相互作用。
Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signaling has been implicated in human birth defects and cancer. Hh signaling is mediated by its N-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog/CDO and the vertebrate-specific proteins Hip and Gas1. Drosophila Ihog and its vertebrate homologs CDO and BOC contain multiple immunoglobulin (Ig) and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that mammalian Sonic hedgehog (ShhN) binds a nonorthologous FNIII repeat of CDO. We report here biochemical, biophysical, and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hot spot for mediating interactions between ShhN and CDO, Ptc, Hip, and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.
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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
影响因子：
64.5
作者：
Ma, Y;Erkner, A;Beachy, PA
通讯作者：
Beachy, PA
影响因子：
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作者：
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DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
11.4
作者：
Kang, JS;Mulieri, PJ;Krauss, RS
通讯作者：
Krauss, RS