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.
Cell. 2018 Nov 15;175(5):1352-1364.e14. doi: 10.1016/j.cell.2018.10.026. Epub 2018 Nov 8.
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.
刺猬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，否则它会抑制 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，它允许 smoothened 和 Hedgehog 途径不受调节的激活。patched 蛋白的低温电镜结构显示出与原核 rnd 转运蛋白惊人的跨膜结构域相似性。一个带有胆固醇样物质的中央疏水性管道穿过细胞外结构域，类似于其他 rnd 蛋白用于转运底物的管道，这表明 patched 蛋白在胆固醇转运中发挥作用。PTCH1 表达降低了质膜内层的胆固醇活性，但 Hedgehog 刺激可迅速恢复，这表明 PTCH1 通过控制胆固醇的可用性来调节 smoothened。
