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| | ==Crystal structure of activated Notch, CSL and MAML on HES-1 promoter DNA sequence== | | ==Crystal structure of activated Notch, CSL and MAML on HES-1 promoter DNA sequence== |
| - | <StructureSection load='2f8x' size='340' side='right' caption='[[2f8x]], [[Resolution|resolution]] 3.25Å' scene=''> | + | <StructureSection load='2f8x' size='340' side='right'caption='[[2f8x]], [[Resolution|resolution]] 3.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2f8x]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F8X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2F8X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2f8x]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F8X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2F8X FirstGlance]. <br> |
| - | </td></tr><tr><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 Homo sapiens]), MAML1, KIAA0200 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.25Å</td></tr> |
| - | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2f8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f8x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2f8x RCSB], [http://www.ebi.ac.uk/pdbsum/2f8x PDBsum]</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=2f8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f8x OCA], [https://pdbe.org/2f8x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2f8x RCSB], [https://www.ebi.ac.uk/pdbsum/2f8x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2f8x 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> [[http://www.uniprot.org/uniprot/SUH_HUMAN SUH_HUMAN]] Defects in RBPJ are the cause of Adams-Oliver syndrome 3 (AOS3) [MIM:[http://omim.org/entry/614814 614814]]. An autosomal dominant form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. AOS3 patients manifest characteristic vertex scalp defects and terminal limb defects, but without congenital heart defects, other associated defects, or immune defects.<ref>PMID:22883147</ref> | + | [https://www.uniprot.org/uniprot/SUH_HUMAN SUH_HUMAN] Defects in RBPJ are the cause of Adams-Oliver syndrome 3 (AOS3) [MIM:[https://omim.org/entry/614814 614814]. An autosomal dominant form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. AOS3 patients manifest characteristic vertex scalp defects and terminal limb defects, but without congenital heart defects, other associated defects, or immune defects.<ref>PMID:22883147</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). [[http://www.uniprot.org/uniprot/SUH_HUMAN SUH_HUMAN]] Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA.<ref>PMID:21991380</ref> [[http://www.uniprot.org/uniprot/MAML1_HUMAN MAML1_HUMAN]] Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.<ref>PMID:11101851</ref> <ref>PMID:11390662</ref> <ref>PMID:12050117</ref> <ref>PMID:15546612</ref> <ref>PMID:17317671</ref> | + | [https://www.uniprot.org/uniprot/SUH_HUMAN SUH_HUMAN] Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA.<ref>PMID:21991380</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f8/2f8x_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f8/2f8x_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2f8x ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 2f8x" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Blacklow, S C.]] | + | [[Category: Large Structures]] |
| - | [[Category: Nam, Y.]] | + | [[Category: Blacklow SC]] |
| - | [[Category: Sliz, P.]] | + | [[Category: Nam Y]] |
| - | [[Category: Ankyrin repeat]] | + | [[Category: Sliz P]] |
| - | [[Category: Csl]]
| + | |
| - | [[Category: Hes-1]]
| + | |
| - | [[Category: Mastermind]]
| + | |
| - | [[Category: Notch]]
| + | |
| - | [[Category: Rel-homology region]]
| + | |
| - | [[Category: Transcription-dna complex]]
| + | |
| Structural highlights
Disease
SUH_HUMAN Defects in RBPJ are the cause of Adams-Oliver syndrome 3 (AOS3) [MIM:614814. An autosomal dominant form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. AOS3 patients manifest characteristic vertex scalp defects and terminal limb defects, but without congenital heart defects, other associated defects, or immune defects.[1]
Function
SUH_HUMAN Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA.[2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Notch receptors transduce essential developmental signals between neighboring cells by forming a complex that leads to transcription of target genes upon activation. We report here the crystal structure of a Notch transcriptional activation complex containing the ankyrin domain of human Notch1 (ANK), the transcription factor CSL on cognate DNA, and a polypeptide from the coactivator Mastermind-like-1 (MAML-1). Together, CSL and ANK create a groove to bind the MAML-1 polypeptide as a kinked, 70 A helix. The composite binding surface likely restricts the recruitment of MAML proteins to promoters on which Notch:CSL complexes have been preassembled, ensuring tight transcriptional control of Notch target genes.
Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.,Nam Y, Sliz P, Song L, Aster JC, Blacklow SC Cell. 2006 Mar 10;124(5):973-83. PMID:16530044[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hassed SJ, Wiley GB, Wang S, Lee JY, Li S, Xu W, Zhao ZJ, Mulvihill JJ, Robertson J, Warner J, Gaffney PM. RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am J Hum Genet. 2012 Aug 10;91(2):391-5. doi: 10.1016/j.ajhg.2012.07.005. PMID:22883147 doi:10.1016/j.ajhg.2012.07.005
- ↑ Bartels SJ, Spruijt CG, Brinkman AB, Jansen PW, Vermeulen M, Stunnenberg HG. A SILAC-based screen for Methyl-CpG binding proteins identifies RBP-J as a DNA methylation and sequence-specific binding protein. PLoS One. 2011;6(10):e25884. doi: 10.1371/journal.pone.0025884. Epub 2011 Oct 3. PMID:21991380 doi:10.1371/journal.pone.0025884
- ↑ Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell. 2006 Mar 10;124(5):973-83. PMID:16530044 doi:10.1016/j.cell.2005.12.037
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