Structural basis for autoinhibition of Notch |
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Authors: | Gordon Wendy R Vardar-Ulu Didem Histen Gavin Sanchez-Irizarry Cheryll Aster Jon C Blacklow Stephen C |
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Affiliation: | Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA. |
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Abstract: | 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. |
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