Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched.,Cell

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Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched.
Cell ( IF 45.5 ) Pub Date : 2018-Nov-15 , DOI: 10.1016/j.cell.2018.10.026
Yunxiao Zhang ₁ , David P Bulkley ₂ , Yao Xin ₃ , Kelsey J Roberts ₄ , Daniel E Asarnow ₂ , Ashutosh Sharma ₃ , Benjamin R Myers ₅ , Wonhwa Cho ₃ , Yifan Cheng ₆ , Philip A Beachy ₇

Affiliation

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94158, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94158, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Biochemistry and Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched, a 12-transmembrane protein that otherwise would suppress the activity of the 7-transmembrane protein Smoothened. Loss of Patched function, the most common cause of basal cell carcinoma, permits unregulated activation of Smoothened and of the Hedgehog pathway. A cryo-EM structure of the Patched protein reveals striking transmembrane domain similarities to prokaryotic RND transporters. A central hydrophobic conduit with cholesterol-like contents courses through the extracellular domain and resembles that used by other RND proteins to transport substrates, suggesting Patched activity in cholesterol transport. Cholesterol activity in the inner leaflet of the plasma membrane is reduced by PTCH1 expression but rapidly restored by Hedgehog stimulation, suggesting that PTCH1 regulates Smoothened by controlling cholesterol availability.

中文翻译：

Hedgehog 受体的胆固醇转运样活性的结构基础已修补。

Hedgehog 蛋白信号通过与其共同受体 Patched 结合并使其失活来介导组织模式形成和维持，Patched 是一种 12 次跨膜蛋白，否则会抑制 7 次跨膜蛋白 Smoothened 的活性。 Patched 功能的丧失是基底细胞癌最常见的原因，导致 Smoothened 和 Hedgehog 通路的激活不受调节。 Patched 蛋白的冷冻电镜结构揭示了与原核 RND 转运蛋白惊人的跨膜结构域相似性。含有类胆固醇内容物的中央疏水管道穿过细胞外结构域，类似于其他 RND 蛋白用于运输底物的管道，表明胆固醇运输中存在补丁活性。 PTCH1 表达降低了质膜内叶中的胆固醇活性，但通过 Hedgehog 刺激迅速恢复，表明 PTCH1 通过控制胆固醇可用性来调节 Smoothened。

更新日期：2018-11-09

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