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Glypicans shield the Wnt lipid moiety to enable signalling at a distance

机译：糖尿病屏蔽Wnt脂肪部分以使信号传递在距离处

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摘要

A relatively small number of proteins have been suggested to act as morphogens-signalling molecules that spread within tissues to organize tissue repair and the specification of cell fate during development. Among them are Wnt proteins, which carry a palmitoleate moiety that is essential for signalling activity(1-3). How a hydrophobic lipoprotein can spread in the aqueous extracellular space is unknown. Several mechanisms, such as those involving lipoprotein particles, exosomes or a specific chaperone, have been proposed to overcome this so-called Wnt solubility problem(4-6). Here we provide evidence against these models and show that the Wnt lipid is shielded by the core domain of a subclass of glypicans defined by the Dally-like protein (Dlp). Structural analysis shows that, in the presence of palmitoleoylated peptides, these glypicans change conformation to create a hydrophobic space. Thus, glypicans of the Dlp family protect the lipid of Wnt proteins from the aqueous environment and serve as a reservoir from which Wnt proteins can be handed over to signalling receptors.Genetic studies inDrosophilacombined with structural analyses show that glypicans bind palmitoylate moieties in Wnt ligands, and thus shield Wnt ligands from their aqueous environments to enable them to signal to their distant receptors.
机译：已经提出了一种相对少量的蛋白质，以充当多酚信令分子，其在组织中扩散以组织组织修复和在发育过程中细胞命运的规范。其中是WNT蛋白质，其携带一种对信号传导活性至关重要的棕榈酸酯部分（1-3）。如何在含水细胞外空间中散布疏水性脂蛋白是未知的。已经提出了几种机制，例如涉及脂蛋白颗粒，外泌体或特异性伴侣的机制，以克服这种所谓的WNT溶解性问题（4-6）。在这里，我们提供针对这些模型的证据，并表明Wnt脂质被由二丙基蛋白（DLP）定义的血型腺亚类的核心结构域屏蔽。结构分析表明，在存在棕榈药酰化肽的情况下，这些血糖化合物改变构象以产生疏水性空间。因此，DLP系列的血糖蛋白保护Wnt蛋白的脂质免受水性环境的脂质，并用作可以将Wnt蛋白传递给信号受体的储层。胰腺癌嗜吸附性与结构分析表明，血糖化合物在WNT配体中结合棕榈酰胺部分，因此，从水环境中屏蔽Wnt配体，使它们能够向其远处的受体发出信号。

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  • 来源
    《Nature》 |2020年第7823期|85-90|共6页
  • 作者

    McGough Ian J.; Vecchia Luca; Bishop Benjamin; Malinauskas Tomas; Beckett Karen; Joshi Dhira; OReilly Nicola; Siebold Christian; Jones E. Yvonne; Vincent Jean-Paul;

  • 作者单位

    Francis Crick Inst London England;

    Univ Oxford Div Struct Biol Wellcome Ctr Human Genet Oxford England;

    Univ Oxford Div Struct Biol Wellcome Ctr Human Genet Oxford England;

    Univ Oxford Div Struct Biol Wellcome Ctr Human Genet Oxford England;

    Francis Crick Inst London England;

    Francis Crick Inst London England;

    Francis Crick Inst London England;

    Univ Oxford Div Struct Biol Wellcome Ctr Human Genet Oxford England;

    Univ Oxford Div Struct Biol Wellcome Ctr Human Genet Oxford England;

    Francis Crick Inst London England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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