Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA.
Nat Chem Biol. 2012 Jan 8;8(2):211-20. doi: 10.1038/nchembio.765.
Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S)-hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. We present several lines of evidence that this protein target is the seven-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing sterol signaling mechanisms.
氧化固醇是一类内源性信号分子，可以激活 Hedgehog 通路，该通路在发育、再生和癌症中具有关键作用。然而，氧化固醇如何影响 Hedgehog 信号通路尚不清楚，包括它们的作用是否通过蛋白靶标介导，还是通过对膜性质的间接影响介导。为了回答这个问题，我们合成了最有效的氧化固醇 20(S)-羟基胆固醇的对映异构体和差向异构体。使用这些分子，我们表明氧化固醇对 Hedgehog 信号通路的影响具有高度的立体选择性，这与它们通过特定蛋白靶标发挥作用的假设一致。我们提出了几条证据表明，该蛋白靶标是七跨膜蛋白 Smoothened，它是肿瘤学中的主要药物靶标。我们的工作表明，这些神秘的固醇可能作为信号受体的配体，对细胞生理学有多种影响，并为探究固醇信号机制提供了一个普遍适用的框架。
