Structures of human Patched and its complex with native palmitoylated sonic hedgehog.
Structures of human Patched and its complex with native palmitoylated sonic hedgehog.
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DOI：
10.1038/s41586-018-0308-7
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发表时间：
2018-08
期刊：
影响因子：
64.8
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Qi X;Schmiege P;Coutavas E;Wang J;Li X
Hedgehog （Hh）信号控制着哺乳动物和其他多细胞生物的胚胎发生和成体组织稳态。虽然Hh信号缺陷导致出生缺陷，但不受限制的Hh信号与人类癌症有关。n端棕榈酰化Hh释放对肿瘤蛋白Smoothened （Smo）的抑制；然而，Hh识别patch的机制尚不清楚。在这里，我们报告了人类patch -1单独和与天然Sonic Hedgehog （sh - n）复合物的低温电镜结构，分别为3.5-Å和3.8-Å分辨率。patch -1的结构在其跨膜核心显示出内部的双重伪对称，具有一个固醇传感结构域（SSD）和两个同源的细胞外结构域（ECDs），类似于Niemann-Pick C1蛋白（NPC1）的结构。sh - n的棕榈酰化n端插入ECDs之间的空腔并主导ptch1 - sh - n界面，这与sh - n共受体的报道不同。值得注意的是，我们的生化分析表明sh - n可能使用另一种界面，这是其共受体结合所必需的，在没有共价附着棕榈酸盐的情况下招募Ptch1。我们的工作提供了Ptch1对Hh- n识别的原子见解，为Hh- n与各种受体的合作结合提供了结构基础，并作为Hh信号传导及其在疾病中的功能障碍的分子框架。
Hedgehog (Hh) signaling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms. Whereas deficient Hh signaling leads to birth defects, unrestrained Hh signaling is implicated in human cancers. N-terminally palmitoylated Hh releases the repression of Patched to the oncoprotein Smoothened (Smo); however, the mechanism by which Hh recognizes Patched is unclear. Here, we report cryo-EM structures of human Patched-1 alone and in complex with native Sonic Hedgehog (Shh-N) at 3.5-Å and 3.8-Å resolution, respectively. The Patched-1 structure reveals internal two-fold pseudo-symmetry in its transmembrane core featuring a sterol-sensing domain (SSD) and two homologous extracellular domains (ECDs), resembling the architecture of Niemann-Pick C1 protein (NPC1). The palmitoylated N-terminus of Shh-N inserts into a cavity between the ECDs and dominates the Ptch1–Shh-N interface, which is distinct from that reported for Shh-N co-receptors. Notably, our biochemical assays show that Shh-N may employ another interface, which is required for its co-receptor binding, to recruit Ptch1 in the absence of covalently attached palmitate. Our work provides atomic insights into Hh-N recognition by Ptch1, offers a structural basis for cooperative binding of Hh-N to various receptors, and serves as a molecular framework for Hh signaling and its malfunction in disease.
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影响因子：
11.8
作者：
Jiang J;Hui CC
通讯作者：
Hui CC
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：
11.8
作者：
Izzi, Luisa;Levesque, Martin;Morin, Steves;Laniel, Dominique;Wilkes, Brian C.;Mille, Frederic;Krauss, Robert S.;McMahon, Andrew P.;Allen, Benjamin L.;Charron, Frederic
通讯作者：
Charron, Frederic
影响因子：
4.8
作者：
Pepinsky, RB;Rayhorn, P;Garber, EA
通讯作者：
Garber, EA
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC