4x9j

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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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.
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The inducible transcription factor Egr-1 binds specifically to 9-bp target sequences containing two CpG sites that can potentially be methylated at four cytosine bases. Although it appears that complete CpG methylation would make an unfavorable steric clash in the previous crystal structures of the complexes with unmethylated or partially methylated DNA, our affinity data suggest that DNA recognition by Egr-1 is insensitive to CpG methylation. We have determined, at a 1.4-A resolution, the crystal structure of the Egr-1 zinc-finger complex with completely methylated target DNA. Structural comparison of the three different methylation states reveals why Egr-1 can recognize the target sequences regardless of CpG methylation.
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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>
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Structural impact of complete CpG methylation within target DNA on specific complex formation of the inducible transcription factor Egr-1.,Zandarashvili L, White MA, Esadze A, Iwahara J FEBS Lett. 2015 May 19. pii: S0014-5793(15)00398-1. doi:, 10.1016/j.febslet.2015.05.022. PMID:25999311<ref>PMID:25999311</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 06:54, 3 June 2015

EGR-1 with Doubly Methylated DNA

4x9j, resolution 1.41Å

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