Neurogenic locus notch homolog protein 3

Function

Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD), it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity).

Classification

Family (Pfam)

PF00023 Ank, PF12796 Ank_2, PF00008 EGF, PF07645 EGF_CA, PF12661 hEGF, PF06816 NOD, PF07684 NODP, PF00066 Notch

InterPro

Ankyrin_rpt, Ankyrin_rpt-contain_sf, EGF, EGF-like_Ca-bd_dom, EGF-like_CS, EGF-type_Asp/Asn_hydroxyl_site, EGF_Ca-bd_CS, Growth_fac_rcpt_cys_sf, Notch, Notch-like_dom_sf, Notch/Slit_guidance, NOTCH1_EGF-like, Notch_3, Notch_C, Notch_dom, Notch_NOD_dom, Notch_NODP_dom

Functional cluster

Venom Serine Proteases & Phospholipase A2

Experimental structures · PDB · 6

• 4ZLP X-ray 2.48A
• 5CZV X-ray 3.19A
• 5CZX X-ray 2.10A
• 6WQU X-ray 2.41A
• 6XSW X-ray 2.98A
• 8OS0 NMR

A predicted model is available from AlphaFold.

Gene Ontology · 20

• GO:0009986 cell surface
• GO:0005829 cytosol
• GO:0005789 endoplasmic reticulum membrane
• GO:0005576 extracellular region
• GO:0000139 Golgi membrane
• GO:0005654 nucleoplasm
• GO:0005886 plasma membrane
• GO:0043235 receptor complex
• GO:0045296 cadherin binding
• GO:0005509 calcium ion binding
• GO:0019899 enzyme binding
• GO:0042802 identical protein binding
• GO:0038023 signaling receptor activity
• GO:0007411 axon guidance
• GO:0006351 DNA-templated transcription
• GO:0072104 glomerular capillary formation
• GO:0007219 Notch signaling pathway
• GO:1902895 positive regulation of miRNA transcription
• GO:0048661 positive regulation of smooth muscle cell proliferation
• GO:0050793 regulation of developmental process

Disease associations

• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 MONDO:0000914
• lateral meningocele syndrome MONDO:0007537
• familial partial lipodystrophy, Kobberling type MONDO:0012072
• myofibromatosis, infantile, 2 MONDO:0014122
• cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 MONDO:0979867

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Neurogenic locus notch homolog protein 3 0.99
• Neurogenic locus notch homolog protein 3 0.99
• Neurogenic locus notch homolog protein 1 0.92
• Neurogenic locus notch homolog protein 2 0.91
• Neurogenic locus notch homolog protein 2 0.91
• Neurogenic locus notch homolog protein 4 0.90
• Neurogenic locus notch homolog protein 1 0.90
• Protein jagged-2 0.90
• Neurogenic locus notch homolog protein 1 0.90
• Neurogenic locus notch homolog protein 1 0.89
• Sushi, nidogen and EGF-like domain-containing protein 1 0.89
• Protein jagged-2 0.89

Co-cited proteins · studied together in the literature

• Neurogenic locus notch homolog protein 4 3 shared papers
• Neurogenic locus notch homolog protein 2 5 shared papers
• Proteasome subunit alpha type-1 1 shared papers
• Platelet-derived growth factor receptor beta 1 shared papers
• Neurogenic locus notch homolog protein 1 4 shared papers
• Neurogenic locus notch homolog protein 3 2 shared papers
• Mastermind-like protein 3 1 shared papers
• Neurogenic locus notch homolog protein 2 2 shared papers
• Mastermind-like protein 1 1 shared papers
• Hypoxia-inducible factor 1-alpha inhibitor 2 shared papers
• Protein jagged-1 1 shared papers
• Mastermind-like protein 2 1 shared papers

Literature · 49 cited papers

• Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways. Diabetes · 2025
• Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants. Neuropediatrics · 2022
• A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke. J. Neurol. · 2021
• Naturally occurring NOTCH3 exon skipping attenuates NOTCH3 protein aggregation and disease severity in CADASIL patients. Hum. Mol. Genet. · 2020
• A Japanese CADASIL patient with homozygous NOTCH3 p.Arg544Cys mutation confirmed pathologically. J. Neurol. Sci. · 2018
• Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family. J. Neurol. Sci. · 2016
• Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy. EMBO Mol. Med. · 2015
• Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. Am. J. Med. Genet. A · 2015
• Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics · 2014
• Hypomorphic NOTCH3 alleles do not cause CADASIL in humans. Hum. Mutat. · 2013
• Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am. J. Hum. Genet. · 2013
• A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain. J. Chin. Med. Assoc. · 2013
• … and 37 more in the literature graph