Gordon Wendy R, Vardar-Ulu Didem, Histen Gavin, Sanchez-Irizarry Cheryll, Aster Jon C, Blacklow Stephen C
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA.
Nat Struct Mol Biol. 2007 Apr;14(4):295-300. doi: 10.1038/nsmb1227. Epub 2007 Apr 1.
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.
Notch受体在相邻细胞间传递信号。当配体结合诱导Notch在细胞外负调控区（NRR）内发生金属蛋白酶切割时，信号传导开始。我们在此展示了人NOTCH2 NRR的X射线结构，其呈现出一种自抑制构象。NRR内广泛的结构域间相互作用掩埋了金属蛋白酶位点，表明在配体激活过程中，需要相当大的构象变化来暴露该位点。NOTCH1中与白血病相关的突变可能通过破坏NRR保守疏水核心的稳定性来释放自抑制。
