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| | <StructureSection load='6od5' size='340' side='right'caption='[[6od5]], [[Resolution|resolution]] 2.05Å' scene=''> | | <StructureSection load='6od5' size='340' side='right'caption='[[6od5]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6od5]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OD5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OD5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6od5]] is a 8 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=6OD5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OD5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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]] 2.05Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=1CC:5-CARBOXY-2-DEOXYCYTIDINE+MONOPHOSPHATE'>1CC</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1CC:5-CARBOXY-2-DEOXYCYTIDINE+MONOPHOSPHATE'>1CC</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TCF4, BHLHB19, ITF2, SEF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6od5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6od5 OCA], [https://pdbe.org/6od5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6od5 RCSB], [https://www.ebi.ac.uk/pdbsum/6od5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6od5 ProSAT]</span></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=6od5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6od5 OCA], [http://pdbe.org/6od5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6od5 RCSB], [http://www.ebi.ac.uk/pdbsum/6od5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6od5 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ITF2_HUMAN ITF2_HUMAN]] Autosomal dominant non-syndromic intellectual disability;Fuchs endothelial corneal dystrophy;Pitt-Hopkins syndrome;Schizophrenia;Primary sclerosing cholangitis. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/ITF2_HUMAN ITF2_HUMAN] Autosomal dominant non-syndromic intellectual disability;Fuchs endothelial corneal dystrophy;Pitt-Hopkins syndrome;Schizophrenia;Primary sclerosing cholangitis. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ITF2_HUMAN ITF2_HUMAN]] Transcription factor that binds to the immunoglobulin enchancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription (By similarity). Preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3'. | + | [https://www.uniprot.org/uniprot/ITF2_HUMAN ITF2_HUMAN] Transcription factor that binds to the immunoglobulin enchancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription (By similarity). Preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3'. |
| | <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: Cheng, X]] | + | [[Category: Cheng X]] |
| - | [[Category: Horton, J R]] | + | [[Category: Horton JR]] |
| - | [[Category: Yang, J]] | + | [[Category: Yang J]] |
| - | [[Category: Bhth]]
| + | |
| - | [[Category: E-box]]
| + | |
| - | [[Category: Protein-dna complex]]
| + | |
| - | [[Category: Transcription factor]]
| + | |
| - | [[Category: Transcription-dna complex]]
| + | |
| Structural highlights
Disease
ITF2_HUMAN Autosomal dominant non-syndromic intellectual disability;Fuchs endothelial corneal dystrophy;Pitt-Hopkins syndrome;Schizophrenia;Primary sclerosing cholangitis. The disease is caused by mutations affecting the gene represented in this entry.
Function
ITF2_HUMAN Transcription factor that binds to the immunoglobulin enchancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription (By similarity). Preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3'.
Publication Abstract from PubMed
The psychiatric risk-associated transcription factor 4 (TCF4) is linked to schizophrenia. Rare TCF4 coding variants are found in individuals with Pitt-Hopkins syndrome-an intellectual disability and autism spectrum disorder. TCF4 contains a C-terminal basic-helix-loop-helix (bHLH) DNA binding domain which recognizes the enhancer-box (E-box) element 5'-CANNTG-3' (where N = any nucleotide). A subset of the TCF4-occupancy sites have the expanded consensus binding specificity 5'-C(A/G)-CANNTG-3', with an added outer Cp(A/G) dinucleotide; for example in the promoter for CNIH3, a gene involved in opioid dependence. In mammalian genomes, particularly brain, the CpG and CpA dinucleotides can be methylated at the 5-position of cytosine (5mC), and then may undergo successive oxidations to the 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC) forms. We find that, in the context of 5'-0CG-1CA-2CG-3TG-3'(where the numbers indicate successive dinucleotides), modification of the central E-box 2CG has very little effect on TCF4 binding, E-box 1CA modification has a negative influence on binding, while modification of the flanking 0CG, particularly carboxylation, has a strong positive impact on TCF4 binding to DNA. Crystallization of TCF4 in complex with unmodified or 5caC-modified oligonucleotides revealed that the basic region of bHLH domain adopts multiple conformations, including an extended loop going through the DNA minor groove, or the N-terminal portion of a long helix binding in the DNA major groove. The different protein conformations enable arginine 576 (R576) to interact, respectively, with a thymine in the minor groove, a phosphate group of DNA backbone, or 5caC in the major groove. The Pitt-Hopkins syndrome mutations affect five arginine residues in the basic region, two of them (R569 and R576) involved in 5caC recognition. Our analyses indicate, and suggest a structural basis for, the preferential recognition of 5caC by a transcription factor centrally important in brain development.
Structural basis for preferential binding of human TCF4 to DNA containing 5-carboxylcytosine.,Yang J, Horton JR, Li J, Huang Y, Zhang X, Blumenthal RM, Cheng X Nucleic Acids Res. 2019 May 13. pii: 5488531. doi: 10.1093/nar/gkz381. PMID:31081034[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yang J, Horton JR, Li J, Huang Y, Zhang X, Blumenthal RM, Cheng X. Structural basis for preferential binding of human TCF4 to DNA containing 5-carboxylcytosine. Nucleic Acids Res. 2019 May 13. pii: 5488531. doi: 10.1093/nar/gkz381. PMID:31081034 doi:http://dx.doi.org/10.1093/nar/gkz381
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