|1toz, 20 NMR models ()|
|Related:||1emo, 1lmj, 1hj7|
NMR structure of the human NOTCH-1 ligand binding region
We present NMR structural and dynamics analysis of the putative ligand binding region of human Notch-1, comprising EGF-like domains 11-13. Functional integrity of an unglycosylated, recombinant fragment was confirmed by calcium-dependent binding of tetrameric complexes to ligand-expressing cells. EGF modules 11 and 12 adopt a well-defined, rod-like orientation rigidified by calcium. The interdomain tilt is similar to that found in previously studied calcium binding EGF pairs, but the angle of twist is significantly different. This leads to an extended double-stranded beta sheet structure, spanning the two EGF modules. Based on the conservation of residues involved in interdomain hydrophobic packing, we propose this arrangement to be prototypical of a distinct class of EGF linkages. On this premise, we have constructed a model of the 36 EGF modules of the Notch extracellular domain that enables predictions to be made about the general role of calcium binding to this region.
Structural and functional properties of the human notch-1 ligand binding region., Hambleton S, Valeyev NV, Muranyi A, Knott V, Werner JM, McMichael AJ, Handford PA, Downing AK, Structure. 2004 Dec;12(12):2173-83. PMID:15576031
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[NOTC1_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.
[NOTC1_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).
About this Structure
- Hambleton S, Valeyev NV, Muranyi A, Knott V, Werner JM, McMichael AJ, Handford PA, Downing AK. Structural and functional properties of the human notch-1 ligand binding region. Structure. 2004 Dec;12(12):2173-83. PMID:15576031 doi:10.1016/j.str.2004.09.012
- Muranyi A, Hambleton S, Knott V, McMichael A, Handford PA, Downing AK. 1H, 13C, and 15N resonance assignments of human Notch-1 calcium binding EGF domains 11-13. J Biomol NMR. 2004 Jul;29(3):443-4. PMID:15213460 doi:10.1023/B:JNMR.0000032521.42723.1a
- Majumder R, Roy S, Thakur AR. Analysis of Delta-Notch interaction by molecular modeling and molecular dynamic simulation studies. J Biomol Struct Dyn. 2012 May;30(1):13-29. PMID:22571430 doi:10.1080/07391102.2012.674184