Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling.
Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling.
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DOI：
10.1038/nchembio.1290
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发表时间：
2013-09
影响因子：
14.8
通讯作者：
Salic, Adrian
中科院分区：
文献类型：
--
作者：
Nedelcu, Daniel;Liu, Jing;Xu, Yangqing;Jao, Cindy;Salic, Adrian
氧化甾醇结合七扳手跨膜蛋白平滑并有效激活脊椎动物刺猬信号，这是胚胎发育，成体干细胞维持和癌症的重要途径。然而，尚不清楚氧甾醇是否对正常脊椎动物的Hedgehog信号传导起重要作用，以及拮抗氧甾醇是否能抑制Hedgehog通路。我们开发了通过结合Smoothened的氧甾醇结合位点阻断Hedgehog信号传导的azasterol。我们发现，氧甾醇和azasterol的结合位点映射到Smoothened的细胞外富含半胱氨酸的区域，并且与Smoothened七螺旋束内的其他小分子调节剂的结合位点完全分离。平滑突变体中，羟甾醇结合被废除不再对羟甾醇作出反应，并且不能被Hedgehog配体最大限度地激活。我们的研究结果表明，脊椎动物Smoothened的正常信号传递需要氧甾醇结合，而靶向氧甾醇结合位点是抑制Smoothened的有效策略。
Oxysterols bind the seven-spanner transmembrane protein Smoothened and potently activate vertebrate Hedgehog signaling, a pathway essential in embryonic development, adult stem cell maintenance and cancer. It is unknown, however, if oxysterols are important for normal vertebrate Hedgehog signaling, and whether antagonizing oxysterols can inhibit the Hedgehog pathway. We developed azasterols that block Hedgehog signaling by binding the oxysterol-binding site of Smoothened. We show that the binding site for oxysterols and azasterols maps to the extracellular, cysteine-rich domain of Smoothened, and is completely separable from the site bound by other small molecule modulators, located within the heptahelical bundle of Smoothened. Smoothened mutants in which oxysterol binding is abolished no longer respond to oxysterols, and cannot be maximally activated by the Hedgehog ligand. Our results show that oxysterol binding to vertebrate Smoothened is required for normal Hedgehog signaling, and that targeting the oxysterol binding site is an effective strategy to inhibit Smoothened.
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影响因子：
56.9
作者：
Rohatgi, Rajat;Milenkovic, Ljiljana;Scott, Matthew P.
通讯作者：
Scott, Matthew P.
DOI：
10.1083/jcb.201004108
发表时间：
2010-10-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Tukachinsky H;Lopez LV;Salic A
通讯作者：
Salic A
影响因子：
64.8
作者：
Corbit, KC;Aanstad, P;Reiter, JF
通讯作者：
Reiter, JF
影响因子：
2.6
作者：
Nakano, Y;Nystedt, S;Ingham, PW
通讯作者：
Ingham, PW
影响因子：
50.3
作者：
Kim J;Tang JY;Gong R;Kim J;Lee JJ;Clemons KV;Chong CR;Chang KS;Fereshteh M;Gardner D;Reya T;Liu JO;Epstein EH;Stevens DA;Beachy PA
通讯作者：
Beachy PA