title: CADASIL Notch3 mutant proteins localize to the cell surface and bind ligand.
abstract: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementia arising from abnormal arteriolar vascular smooth muscle cells. CADASIL results from mutations in Notch3 that alter the number of cysteine residues in the extracellular epidermal growth factor-like repeats, important for ligand binding. It is not known whether CADASIL mutations lead to loss or gain of Notch3 receptor function. To examine the functional consequences of CADASIL mutations, we engineered 4 CADASIL-like mutations into rat Notch3 and have shown that the presence of an unpaired cysteine does not impair cell-surface expression or ligand binding.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles 90095, USA.
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Jim
authors.initials: J
authors.lastname: Boulter
authors.forename: Carol
authors.initials: C
authors.lastname: Hicks
authors.forename: Jonathon
authors.initials: J
authors.lastname: Buhrman
authors.forename: Guy
authors.initials: G
authors.lastname: DiSibio
authors.forename: Carrie
authors.initials: C
authors.lastname: Shawber
authors.forename: Gerry
authors.initials: G
authors.lastname: Weinmaster
authors.forename: Donna
authors.initials: D
authors.lastname: Nofziger
authors.forename: Carolyn
authors.initials: C
authors.lastname: Schanen
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D015161:Dementia, Multi-Infarct / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D008024:Ligands; C499374:NOTCH3 protein, human; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; C073572:Notch4 protein, mouse