Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.
Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.
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DOI：
10.1016/j.devcel.2022.02.008
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发表时间：
2022-03-14
影响因子：
11.8
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Huang P;Wierbowski BM;Lian T;Chan C;García-Linares S;Jiang J;Salic A
双脂化的Sonic hedgehog （SHH）形态原通过肿瘤抑制膜蛋白Patched1 （PTCH1）发出信号，激活hedgehog通路，这是发育和癌症的基础。SHH与PTCH1的结合需要GAS1共受体，但其机制尚不清楚。我们证明了GAS1的独特作用，通过将SHH从细胞外SCUBE2载体直接转移到PTCH1，催化脊椎动物细胞中sh - PTCH1复合物的组装。GAS1 - sh - PTCH1过渡状态的结构确定了GAS1如何以模块化方式识别SHH棕榈酸酯和胆固醇修饰，以及它如何促进脂质依赖性SHH向PTCH1的传递。结构导向实验阐明了SHH从SCUBE2到PTCH1的运动，解释了疾病突变，并证明SHH诱导的PTCH1二聚化导致其从细胞表面内化。这些结果定义了信号通路sh - ptch1复合体是如何组装的，这是触发Hedgehog通路的关键步骤，并为理解形态因子的接受及其调控提供了一个范例。Huang等人阐明了GAS1共受体如何通过顺序传递催化SHH激活Hedgehog通路。GAS1接受来自细胞外SCUBE2的双脂化SHH，然后短暂的GAS1 - PTCH1相互作用促进SHH向PTCH1转移，导致其抑制。随后shh介导的PTCH1二聚化驱动SHH-PTCH1从细胞表面内化。
The dually lipidated Sonic hedgehog (SHH) morphogen signals through the tumor suppressor membrane protein Patched1 (PTCH1), to activate the Hedgehog pathway, which is fundamental in development and cancer. SHH engagement with PTCH1 requires the GAS1 coreceptor, but the mechanism is unknown. We demonstrate a unique role for GAS1, catalyzing SHH–PTCH1 complex assembly in vertebrate cells by direct SHH transfer from the extracellular SCUBE2 carrier to PTCH1. Structure of the GAS1–SHH–PTCH1 transition state identifies how GAS1 recognizes the SHH palmitate and cholesterol modifications in modular fashion, and how it facilitates lipid-dependent SHH handoff to PTCH1. Structure-guided experiments elucidate SHH movement from SCUBE2 to PTCH1, explain disease mutations, and demonstrate that SHH-induced PTCH1 dimerization causes its internalization from the cell surface. These results define how the signaling-competent SHH–PTCH1 complex assembles, the key step triggering the Hedgehog pathway, and provide a paradigm for understanding morphogen reception and its regulation. Huang et al. elucidate how the GAS1 coreceptor catalyzes Hedgehog pathway activation by SHH, via sequential handoffs. GAS1 accepts dually-lipidated SHH from extracellular SCUBE2, then a transient GAS1–PTCH1 interaction promotes SHH transfer to PTCH1, causing its inhibition. Subsequent SHH-mediated PTCH1 dimerization drives SHH–PTCH1 internalization from the cell surface.
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影响因子：
2.7
作者：
Hollway, Georgina E.;Maule, John;Currie, Peter D.
通讯作者：
Currie, Peter D.
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：
16.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Gong, Xin;Qian, Hongwu;Yan, Nieng
通讯作者：
Yan, Nieng
影响因子：
11.8
作者：
Allen, Benjamin L.;Song, Jane Y.;Izzi, Luisa;Althaus, Irene W.;Kang, Jong-Sun;Charron, Frederic;Krauss, Robert S.;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.