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Dispatched uses Na~+ flux to power release of lipid-modified Hedgehog

机译：调度使用NA〜+通量发电脂质改性的刺猬

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摘要

The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters(1,2) and to H+-driven transporters of the RND family(3,4), enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression(5-10). Here we determine a cryo-electron microscopy structure of the mouse protein Dispatched homologue 1 (DISP1), revealing three Na+ ions coordinated within a channel that traverses its transmembrane domain. We find that the rate of Hedgehog export is dependent on the Na+ gradient across the plasma membrane. The transmembrane channel and Na+ binding are disrupted in DISP1-NNN, a variant with asparagine substitutions for three intramembrane aspartate residues that each coordinate and neutralize the charge of one of the three Na+ ions. DISP1-NNN and variants that disrupt single Na+ sites retain binding to, but are impaired in export of the lipid-modified Hedgehog protein to the SCUBE2 acceptor. Interaction of the amino-terminal signalling domain of the Sonic hedgehog protein (ShhN) with DISP1 occurs via an extensive buried surface area and contacts with an extended furin-cleaved DISP1 arm. Variability analysis reveals that ShhN binding is restricted to one extreme of a continuous series of DISP1 conformations. The bound and unbound DISP1 conformations display distinct Na+-site occupancies, which suggests a mechanism by which transmembrane Na+ flux may power extraction of the lipid-linked Hedgehog signal from the membrane. Na+-coordinating residues in DISP1 are conserved in PTCH1 and other metazoan RND family members, suggesting that Na+ flux powers their conformationally driven activities.
机译：调度蛋白质与NPC1和PTCH1胆固醇转运蛋白（1,2）和RND家族（3,4）的H + -Drunive运输器相关，使得通过释放脂质改性的刺猬蛋白的组织 - 图案化活性来自胚胎表达的紧密 - 划分的位点（5-10）。在这里，我们确定小鼠蛋白质调度同源物的冷冻电子显微镜结构（DISP1），揭示了在穿过其跨膜结构域的通道内配位的三个Na +离子。我们发现刺猬出口率取决于血浆膜上的Na +梯度。跨膜通道和Na +结合在DISP1-NNN中被破坏，该变体，用于三个intarymemmane天冬氨酸残基的天冬酰胺取代，其每个坐标和中和三种Na +离子中的一个。 DISP1-NNN和变体破坏单个NA +位点保留结合，但在将脂质改性的刺猬蛋白的出口到SCUBE2受体中受损。 Sonic Hedgehog蛋白（SHHN）的氨基末端信号域与DISP1的相互作用通过广泛的掩埋表面积和与延伸的Furin-Cleaved DISP1臂的触点发生。可变性分析表明，SHHN结合仅限于连续系列DISP1构象的一个极端。绑定和未绑定的DISP1构象显示了不同的NA + -Site占用，这表明跨膜NA +通量可以从膜中提取脂质连接的血脂信号的机制。 Na + -Coordinating在DASP1中的残留物在PTCH1和其他Metazoan RND家庭成员中保存，表明NA +通量为其构象驱动的活动供电。

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  • 来源
    《Nature》 |2021年第7884期|320-324|共5页
  • 作者

    Wang Qianqian; Asarnow Daniel E.; Ding Ke; Mann Randall K.; Hatakeyama Jason; Zhang Yunxiao; Ma Yong; Cheng Yifan; Beachy Philip A.;

  • 作者单位

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA;

    Univ Calif San Francisco Dept Biochem & Biophys San Francisco CA 94110 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Scripps Res Inst Neurosci Dept Howard Hughes Med Inst La Jolla CA USA;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA|Chinese Acad Sci Suzhou Inst Biomed Engn & Technol Suzhou Peoples R China;

    Univ Calif San Francisco Dept Biochem & Biophys San Francisco CA 94110 USA|Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94110 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Stanford Univ Sch Med Dept Urol Stanford CA 94305 USA|Stanford Univ Sch Med Dept Dev Biol Stanford CA 94305 USA;

  • 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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