Figure 3.

Structure of NOTCH3 receptor protein. NOTCH3 receptor is a non-covalent heterodimer of the extracellular domain (N3ECD) and intracellular domain (N3ICD). N3ECD contains the signal peptide (SP), 34 epidermal growth factor-like repeats (EGFr), of which the 10–11th ones are the ligand binding domain (shaded) and Lin-12/Notch repeat (LNR). N3ICD contains the RBPjκ association module (RAM), ankyrin repeat (ANK), and nuclear localizing sequence (NLS), and is rich in proline (P), glutamate (E), serine (S), and threonine (T) (PEST) domains. The S2 cleavage site (S2) by “a disintegrin and metalloproteinases” (ADAM) protease and intramembrane S3 cleavage site (S3) by γ-secretase are shown. NOTCH3 mutations reported in CADASIL (Section 2.5 and HGMD Professional 2023.3 [54]) and bi-allelic loss-of-function mutations reported in autosomal recessive early-onset arteriopathy (see Section 5.1) [55,56,57] and their localizations are shown.