5kzo | pdb_00005kzo
Notch1 transmembrane and associated juxtamembrane segment
Structural highlights
DiseaseNOTC1_HUMAN Defects in NOTCH1 are a cause of aortic valve disease 1 (AOVD1) [MIM:109730. A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.[1] FunctionNOTC1_HUMAN 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. May be important for normal lymphocyte function. In altered form, may contribute to transformation or progression in some T-cell neoplasms. Involved in the maturation of both CD4+ and CD8+ cells in the thymus. May be important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, may function as a receptor for neuronal DNER and may be involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May enhance HIF1A function by sequestering HIF1AN away from HIF1A (By similarity). Publication Abstract from PubMedgamma-Secretase cleavage of the Notch receptor transmembrane domain is a critical signaling event for various cellular processes. Efforts to develop inhibitors of gamma-secretase cleavage of the amyloid-beta precursor C99 protein as potential Alzheimer's disease therapeutics have been confounded by toxicity resulting from the inhibition of normal cleavage of Notch. We present biochemical and structural data for the combined transmembrane and juxtamembrane Notch domains (Notch-TMD) that illuminate Notch signaling and that can be compared and contrasted with the corresponding traits of C99. The Notch-TMD and C99 have very different conformations, adapt differently to changes in model membrane hydrophobic span, and exhibit different cholesterol-binding properties. These differences may be exploited in the design of agents that inhibit cleavage of C99 while allowing Notch cleavage. Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains.,Deatherage CL, Lu Z, Kroncke BM, Ma S, Smith JA, Voehler MW, McFeeters RL, Sanders CR Sci Adv. 2017 Apr 12;3(4):e1602794. doi: 10.1126/sciadv.1602794. eCollection 2017, Apr. PMID:28439555[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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