Ligand binding induces a conformational change in NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of the receptor-attached ubiquitinated ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and triggers cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3 (Groot et al. 2014). The extracellular NOTCH3 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
Groot, AJ, Habets, R, Vooijs, M, Saftig, P, Hodin, CM, Theys, J, Reiss, K, Yahyanejad, S
metallopeptidase activity of ADAM10:Zn2+ [plasma membrane]
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