View source for 6od4


==Human TCF4 C-terminal bHLH domain in Complex with 11-bp Oligonucleotide Containing E-box Sequence==
<StructureSection load='6od4' size='340' side='right'caption='[[6od4]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6od4]] is a 6 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=6OD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OD4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.699&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=6od4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6od4 OCA], [https://pdbe.org/6od4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6od4 RCSB], [https://www.ebi.ac.uk/pdbsum/6od4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6od4 ProSAT]</span></td></tr>
</table>
== Disease ==
[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 ==
[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;">
== 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<ref>PMID:31081034</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6od4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cheng X]]
[[Category: Horton JR]]
[[Category: Yang J]]