Structural basis for autoinhibition of Notch
Structural basis for autoinhibition of Notch
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DOI：
10.1038/nsmb1227
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发表时间：
2007-04-01
影响因子：
16.8
通讯作者：
Blacklow, Stephen C.
中科院分区：
文献类型：
--
作者：
Gordon, Wendy R.;Vardar-Ulu, Didem;Blacklow, Stephen C.
Notch受体在相邻细胞之间传递信号。当配体结合诱导细胞外负调控区（NRR）内Notch的金属蛋白酶切割时，信号传导开始。我们在这里提出的X射线结构的人NOTCH2 NRR，它采用了自抑制构象。广泛的域间相互作用内的NRR掩埋的金属蛋白酶网站，显示了大量的构象运动是必要的，以暴露该网站在激活配体。白血病相关的NOTCH1突变可能通过破坏NRR保守的疏水核心释放自身抑制。
Notch receptors transmit signals between adjacent cells. Signaling is initiated when ligand binding induces metalloprotease cleavage of Notch within an extracellular negative regulatory region (NRR). We present here the X-ray structure of the human NOTCH2 NRR, which adopts an autoinhibited conformation. Extensive interdomain interactions within the NRR bury the metalloprotease site, showing that a substantial conformational movement is necessary to expose this site during activation by ligand. Leukemia-associated mutations in NOTCH1 probably release autoinhibition by destabilizing the conserved hydrophobic core of the NRR.