View source for 4r2r


==Wilms Tumor Protein (WT1) zinc fingers in complex with carboxylated DNA==
<StructureSection load='4r2r' size='340' side='right'caption='[[4r2r]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4r2r]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R2R 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]] 2.089&#8491;</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=5CM:5-METHYL-2-DEOXY-CYTIDINE-5-MONOPHOSPHATE'>5CM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4r2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r2r OCA], [https://pdbe.org/4r2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r2r RCSB], [https://www.ebi.ac.uk/pdbsum/4r2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r2r ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/WT1_HUMAN WT1_HUMAN] Defects in WT1 are the cause of Frasier syndrome (FS) [MIM:[https://omim.org/entry/136680 136680]. FS is characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant.<ref>PMID:10571943</ref>   Defects in WT1 are the cause of Wilms tumor 1 (WT1) [MIM:[https://omim.org/entry/194070 194070]. WT is an embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms.<ref>PMID:1317572</ref> <ref>PMID:9108089</ref> <ref>PMID:9529364</ref> <ref>PMID:15150775</ref>   Defects in WT1 are the cause of Denys-Drash syndrome (DDS) [MIM:[https://omim.org/entry/194080 194080]. DDS is a typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic.<ref>PMID:9529364</ref> <ref>PMID:1655284</ref> <ref>PMID:1302008</ref> <ref>PMID:1338906</ref> <ref>PMID:8388765</ref> <ref>PMID:8111391</ref> <ref>PMID:8295405</ref> <ref>PMID:8411073</ref> <ref>PMID:8112732</ref> <ref>PMID:8741319</ref> <ref>PMID:8956030</ref> <ref>PMID:9475094</ref> <ref>PMID:10738002</ref> <ref>PMID:11182928</ref> <ref>PMID:10799199</ref> <ref>PMID:11519891</ref> <ref>PMID:15349765</ref>   Defects in WT1 are the cause of nephrotic syndrome type 4 (NPHS4) [MIM:[https://omim.org/entry/256370 256370]. A renal disease characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen.<ref>PMID:9529364</ref> <ref>PMID:11182928</ref> <ref>PMID:9607189</ref> <ref>PMID:15253707</ref>   Defects in WT1 are a cause of Meacham syndrome (MEACHS) [MIM:[https://omim.org/entry/608978 608978]. Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities.<ref>PMID:17853480</ref>   Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1.  Defects in WT1 may be a cause of mesothelioma malignant (MESOM) [MIM:[https://omim.org/entry/156240 156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.<ref>PMID:8401592</ref> 
== Function ==
[https://www.uniprot.org/uniprot/WT1_HUMAN WT1_HUMAN] Transcription factor that plays an important role in cellular development and cell survival. Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. Recognizes and binds to the DNA sequence 5'-CGCCCCCGC-3'. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors. Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing. Isoform 1 has lower affinity for DNA, and can bind RNA.<ref>PMID:19123921</ref> <ref>PMID:19416806</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In mammalian DNA, cytosine occurs in several chemical forms, including unmodified cytosine (C), 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5mC is a major epigenetic signal that acts to regulate gene expression. 5hmC, 5fC, and 5caC are oxidized derivatives that might also act as distinct epigenetic signals. We investigated the response of the zinc finger DNA-binding domains of transcription factors early growth response protein 1 (Egr1) and Wilms tumor protein 1 (WT1) to different forms of modified cytosine within their recognition sequence, 5'-GCG(T/G)GGGCG-3'. Both displayed high affinity for the sequence when C or 5mC was present and much reduced affinity when 5hmC or 5fC was present, indicating that they differentiate primarily oxidized C from unoxidized C, rather than methylated C from unmethylated C. 5caC affected the two proteins differently, abolishing binding by Egr1 but not by WT1. We ascribe this difference to electrostatic interactions in the binding sites. In Egr1, a negatively charged glutamate conflicts with the negatively charged carboxylate of 5caC, whereas the corresponding glutamine of WT1 interacts with this group favorably. Our analyses shows that zinc finger proteins (and their splice variants) can respond in modulated ways to alternative modifications within their binding sequence.

Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence.,Hashimoto H, Olanrewaju YO, Zheng Y, Wilson GG, Zhang X, Cheng X Genes Dev. 2014 Sep 25. pii: gad.250746.114. PMID:25258363<ref>PMID:25258363</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4r2r" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Cheng X]]
[[Category: Hashimoto H]]
[[Category: Olanrewaju YO]]
[[Category: Wilson GG]]
[[Category: Zhang X]]
[[Category: Zheng Y]]