Models for normal Notch activation and aberrant activation by T-ALL mutations. (A) Ligand-mediated Notch activation. Ligand binding triggers a conformational movement that first disengages the LNR and HD domains. Without the stabilizing interactions provided by the LNR domain, the HD domain then relaxes locally or globally to expose the S2 site. (B) H1545P and other interface mutations promote disengagement of the LNR/HD interface. This step then allows local or global HD relaxation to expose the S2 site in a manner analogous to ligand binding. (C) Core mutations directly destabilize the HD domain, precluding stable interaction with the LNR domain and promoting exposure of S2. Extremely destabilizing mutations such as those of class 1A may lead to complete HD dissociation.