Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release.
Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release.
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DOI：
10.1038/s41467-021-27257-w
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发表时间：
2021-11-29
影响因子：
16.6
通讯作者：
Gong X
中科院分区：
文献类型：
--
作者：
Li W;Wang L;Wierbowski BM;Lu M;Dong F;Liu W;Li S;Wang P;Salic A;Gong X
膜蛋白Disp属于RND小分子转运体家族，通过催化细胞外释放棕榈酸酯和胆固醇修饰的HH配体，对Hedgehog(HH)信号转导起重要作用。DISP的功能需要Furin介导的胞外区的蛋白水解性切割，但这如何激活DIP仍不清楚。在这里，我们使用冷冻电子显微镜来确定人Disp1(HDisp1)的原子结构，切割前后，以及在与脂质修饰的Sonic Hedgehog(Shh)配体的络合物中。这些结构与生化数据一起表明，蛋白水解性切割打开了hDisp1的胞外域，消除了空间位阻对Shh结合的阻碍。结构导向功能实验证实了hDisp1-Shh相互作用在配体释放中的作用。我们的结果阐明了hDisp1激活和Shh形态原释放的机制，并强调了独特的蛋白水解性切割事件如何使小分子转运蛋白家族的成员能够获得蛋白质底物。派遣(Disp)RND转运体，由Furin介导的蛋白水解性切割激活，介导脂质修饰的Hedgehog(HH)配体的释放。在这里，作者报道了人Disp1(HDisp1)在切割前后的结构，以及与脂质修饰的Sonic Hedgehog(Shh)的复合体，并对hDisp1的激活和功能机制进行了深入的研究。
The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- and cholesterol-modified Hh ligands from producing cells. Disp function requires Furin-mediated proteolytic cleavage of its extracellular domain, but how this activates Disp remains obscure. Here, we employ cryo-electron microscopy to determine atomic structures of human Disp1 (hDisp1), before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh) ligand. These structures, together with biochemical data, reveal that proteolytic cleavage opens the extracellular domain of hDisp1, removing steric hindrance to Shh binding. Structure-guided functional experiments demonstrate the role of hDisp1–Shh interactions in ligand release. Our results clarify the mechanisms of hDisp1 activation and Shh morphogen release, and highlight how a unique proteolytic cleavage event enabled acquisition of a protein substrate by a member of a family of small molecule transporters. Dispatched (Disp) RND transporter, activated by Furin-mediated proteolytic cleavage, mediates the release of the lipid-modified Hedgehog (Hh) ligands. Here, the authors report structures of human Disp1 (hDisp1) before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh), with insights into the mechanisms of hDisp1 activation and function.
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影响因子：
4.6
作者：
Etheridge, L. Alton;Crawford, T. Quinn;Roelink, Henk
通讯作者：
Roelink, Henk
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
2.2
作者：
Chen, Shaoxia;McMullan, Greg;Faruqi, Abdul R.;Murshudov, Garib N.;Short, Judith M.;Scheres, Sjors H. W.;Henderson, Richard
通讯作者：
Henderson, Richard
影响因子：
56.9
作者：
Gong, Xin;Qian, Hongwu;Yan, Nieng
通讯作者：
Yan, Nieng
DOI：
10.1073/pnas.96.20.10992
发表时间：
1999-09-28
影响因子：
11.1
作者：
Fuse, N;Maiti, T;Beachy, PA
通讯作者：
Beachy, PA