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The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla

机译：刺猬与Ihog同源物结合的模式在不同门中并不保守

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摘要

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 signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-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 (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gasl (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immuno-globulin 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 a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report 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 hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gasl. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type Al map to this calcium-binding site and disrupt interactions with these partners.
机译：刺猬（Hh）蛋白通过形成从表达的离散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的组织模式。细胞对Hh的反应和Hh在组织中的移动均受到精确调节，并且异常的Hh信号传导与人类出生缺陷和癌症有关。 Hh信号传导由其氨基末端结构域（HhN）介导，该结构被双重脂化并作为多价脂蛋白颗粒的一部分分泌。 HhN信号的接收受到应答细胞上几种细胞表面蛋白的调节，包括修补蛋白（Ptc），平滑蛋白（Smo），Ihog（在哺乳动物中称为CDO或CDON）和脊椎动物特异性蛋白Hip（也称为Hhip） ）和Gasl（参考11）。果蝇Ihog及其脊椎动物同源物CDO和BOC包含多个免疫球蛋白和纤连蛋白III型（FNIII）重复序列，而Ihog的第一个FNIII重复序列以肝素依赖性方式结合果蝇HhN。出人意料的是，下拉实验表明哺乳动物的Sonic刺猬N末端域（ShhN）结合了CDO的非直系FNIII重复序列。在这里，我们报道了ShhN和CDO的第三个FNIII重复序列之间的复合物的生化，生物物理和X射线结构研究。我们显示，ShhN-CDO相互作用完全不同于HhN-Ihog相互作用，并且需要钙，该钙结合在ShhN上以前未被发现的位点上。这个位点在几乎所有的Hh蛋白中都是保守的，是介导ShhN与CDO，Ptc，Hip和Gasl之间相互作用的热点。脊椎动物Hh蛋白中引起全前脑型和近距离近距离型Al的突变会映射到该钙结合位点，并破坏与这些伴侣的相互作用。

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