Ligand binding induces a conformational change in NOTCH1, probably through mechanical stretching of NOTCH1 triggered by endocytosis of the ligand attached to the receptor. This conformational change exposes the S2 site in the extracellular region of NOTCH1 and results in cleavage of NOTCH1 by ADAM10 metalloprotease, the mammalian homolog of Kuzbanian (Pan and Rubin, 1997), generating the membrane-anchored NOTCH1 fragment NEXT1.This model is supported by the crystal structure of human NOTCH2 negative regulatory region, showing that NOTCH adopts an autoinhibited conformation where extensive interdomain interactions within the negative regulatory region bury S2. A substantial conformational movement, triggered by ligand binding in trans, is needed to expose S2 (Gordon et al. 2007). After S2 cleavage, the extracellular NOTCH1 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. ADAM17 is able to perform cleavage at the S2 site in vitro (Brou et al. 2000), but ADAM10 was shown to be necessary in studies done on mouse cell lines deficient in different ADAM enzymes (van Tetering et al. 2009). Adam10 knockout mice die at embryonic day 9.5 with multiple defects in the developing central nervous system, somites and cardiovascular system and exhibit decreased expression of the Notch target Hes5 in the neural tube (Hartmann et al. 2002).
Hartmann, D, De Strooper, B, Herreman, A, Lena Illert, A, Saftig, P, Lübke, T, von Figura, K, Craessaerts, K, Umans, L, Annaert, W, Serneels, L
Pan, D, Rubin, GM
Bessia, C, Black, RA, Roux, P, LeBail, O, Doedens, JR, Gupta, N, Brou, C, Israel, A, Logeat, F, Cumano, A
Blacklow, SC, Vardar-Ulu, D, Sanchez-Irizarry, C, Aster, JC, Gordon, WR, Histen, G
Kopan, R, Verlaan, I, van Tetering, G, van der Wall, E, Vooijs, M, van Diest, P
metallopeptidase activity of ADAM10/17:Zn2+ [plasma membrane]
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