Figure 2.
Figure 2. Oncogenic forms of NOTCH1 in T-ALL. Aberrant activation of NOTCH signaling can be triggered by mutations in the NOTCH1 gene. (a) Structure of the wild-type NOTCH1 receptor. Functional domains of NOTCH1 are annotated. (b) Translocations of NOTCH1 to the TCR loci induce the expression of truncated forms of NOTCH1. (c) NOTCH1 HD class1 mutations destabilize the structure of the HD-LNR repeats responsible for maintaining the receptor in resting configuration. (d) The NOTCH1 H1545P mutation impairs the protection of the S2 cleavage site by the HD-LNR repeat complex. (e) NOTCH1 HD class2 mutations displace the S2 metalloprotease cleavage site outside the HD-LNR complex. (f) NOTCH1 JME alleles increase the separation of the HD-LNR repeat complex from the membrane. (g) NOTCH1 ΔPEST mutations delete the C-terminal part of the receptor and impairing the degradation of activated NOTCH1 in the nucleus.
 EGF-like indicates EGF-like repeats; HD, heterodimerization domain; LNR, LNR repeats; RAM, RAM domain; Ankyrin, ankyrin repeats; TAD, transactivation domain; PEST, PEST domain; S2, metalloprotease cleavage site (green); S3, γ-secretase cleavage site (yellow). Sequences altered by the different NOTCH1 mutations are highlighted in red.

Oncogenic forms of NOTCH1 in T-ALL. Aberrant activation of NOTCH signaling can be triggered by mutations in theNOTCH1gene. (a) Structure of the wild-type NOTCH1 receptor. Functional domains of NOTCH1 are annotated. (b) Translocations of NOTCH1 to the TCR loci induce the expression of truncated forms of NOTCH1. (c) NOTCH1 HD class1 mutations destabilize the structure of the HD-LNR repeats responsible for maintaining the receptor in resting configuration. (d) The NOTCH1 H1545P mutation impairs the protection of the S2 cleavage site by the HD-LNR repeat complex. (e) NOTCH1 HD class2 mutations displace the S2 metalloprotease cleavage site outside the HD-LNR complex. (f) NOTCH1 JME alleles increase the separation of the HD-LNR repeat complex from the membrane. (g) NOTCH1 ΔPEST mutations delete the C-terminal part of the receptor and impairing the degradation of activated NOTCH1 in the nucleus.
 EGF-like indicates EGF-like repeats; HD, heterodimerization domain; LNR, LNR repeats; RAM, RAM domain; Ankyrin, ankyrin repeats; TAD, transactivation domain; PEST, PEST domain; S2, metalloprotease cleavage site (green); S3, γ-secretase cleavage site (yellow). Sequences altered by the different NOTCH1 mutations are highlighted in red.

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