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| | ==Notch1 transmembrane and associated juxtamembrane segment== | | ==Notch1 transmembrane and associated juxtamembrane segment== |
| - | <StructureSection load='5kzo' size='340' side='right'caption='[[5kzo]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''> | + | <StructureSection load='5kzo' size='340' side='right'caption='[[5kzo]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5kzo]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KZO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KZO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5kzo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KZO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KZO FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOTCH1, TAN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kzo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kzo OCA], [http://pdbe.org/5kzo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kzo RCSB], [http://www.ebi.ac.uk/pdbsum/5kzo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kzo ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kzo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kzo OCA], [https://pdbe.org/5kzo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kzo RCSB], [https://www.ebi.ac.uk/pdbsum/5kzo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kzo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/NOTC1_HUMAN NOTC1_HUMAN]] Defects in NOTCH1 are a cause of aortic valve disease 1 (AOVD1) [MIM:[http://omim.org/entry/109730 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.<ref>PMID:16025100</ref> | + | [https://www.uniprot.org/uniprot/NOTC1_HUMAN NOTC1_HUMAN] Defects in NOTCH1 are a cause of aortic valve disease 1 (AOVD1) [MIM:[https://omim.org/entry/109730 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.<ref>PMID:16025100</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NOTC1_HUMAN 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). | + | [https://www.uniprot.org/uniprot/NOTC1_HUMAN 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). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Deatherage, C L]] | + | [[Category: Deatherage CL]] |
| - | [[Category: Kroncke, B]] | + | [[Category: Kroncke B]] |
| - | [[Category: Lu, Z]] | + | [[Category: Lu Z]] |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Notch]]
| + | |
| - | [[Category: Transcription]]
| + | |
| Structural highlights
Disease
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.[1]
Function
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).
Publication Abstract from PubMed
gamma-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
- ↑ Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005 Sep 8;437(7056):270-4. Epub 2005 Jul 17. PMID:16025100 doi:10.1038/nature03940
- ↑ Deatherage CL, Lu Z, Kroncke BM, Ma S, Smith JA, Voehler MW, McFeeters RL, Sanders CR. Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains. Sci Adv. 2017 Apr 12;3(4):e1602794. doi: 10.1126/sciadv.1602794. eCollection 2017, Apr. PMID:28439555 doi:http://dx.doi.org/10.1126/sciadv.1602794
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