Fig. 2: NOTCH3 EGFr domain disruption by p.Arg1231Cys.
From: NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
Shown is NOTCH3 p.Arg1231 in context of human NOTCH3 protein domains and cross-species alignment of NOTCH3 amino acid sequences. A Human NOTCH3 Protein Domains. Shown is the position of the associated variant in context of transcript exons (top, alternating blue and purple with numbering) and protein domains (bottom, color coded). NOTCH3 can be divided into four major regions, from left-to-right the signal peptide (light blue), the extra-cellular domain (ECD, brown), the transmembrane domain (orange), and the intra-cellular domain (ICD, blue). The majority of the ECD is composed of n = 34 Epidermal Growth Factor-like repeat (EGFr) domains (in purple with white numbers). Domains involved in signaling are highlighted, including EGFr domains 10 to 11 involved in ligand binding (light purple, numbered), three cleavage domains (S1 in yellow, S2 in yellow with diagonal black stripes, S3 in yellow with black horizontal stripes), and three Lin12/NOTCH repeats (light green, numbered). The ICD contains the Recombination signal-binding protein for Ig of κ region (RAM) domain for transcription factor interaction (green and white checkers), the Nuclear Localization Sequences (NLS, orange with black stripes), five Ankyrin repeats involved in signal transduction (green with white numbers), and the Proline, glutamic acid, serine, and threonine-rich (PEST) domain essential for degradation (green with white stripes). The p.Arg1231Cys variant (red line top to bottom) removes a disulfide-bridge-forming cysteine in the 31st EGFr domain of the ECD, coded by the 22nd exon. B Cross-species Alignment of NOTCH3 (EGFr) Domain # 31 Amino Acid Sequences calculated using BLAST. Shown is an amino acid alignment of 31st EGFr domain of NOTCH3 (human sequence amino acids 1205 to 1244), including (top-to-bottom) human reference, human p.Arg1231Cys mutant, chimpanzee (Pan troglodytes), mouse (Mus musculus), zebrafish (Danio rerio), western clawed frog (Xenopus tropicalis), and green sea turtle (Chelonia mvdas), indicating conservation of the arginine (R) at position 1231 in mammals. Highly-conserved cysteine (C) residues (normally 6 per EGFr) are highlighted in yellow.
