6e93

Crystal Structure of ZBTB38 C-terminal Zinc Fingers 6-9 in complex with methylated DNA

spinqualitylabelsall models 6e93, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6e93 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ZN NonStd Res: 5CM Gene: ZBTB38 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ZBT38_HUMAN] Transcriptional regulator with bimodal DNA-binding specificity. Binds with a higher affinity to methylated CpG dinucleotides in the consensus sequence 5'-CGCG-3' but can also bind to E-box elements (5'-CACGTG-3'). Can also bind specifically to a single methyl-CpG pair. Represses transcription in a methyl-CpG-dependent manner (PubMed:16354688). Plays an important role in regulating DNA replication and common fragile sites (CFS) stability in a RBBP6- and MCM10-dependent manner; represses expression of MCM10 which plays an important role in DNA-replication (PubMed:24726359). Acts as a transcriptional activator. May be involved in the differentiation and/or survival of late postmitotic neurons (By similarity).[UniProtKB:Q5EXX3] Publication Abstract from PubMed Methyl-CpG binding proteins (MBPs) are selective readers of DNA methylation that play an essential role in mediating cellular transcription processes in both normal and diseased cells. This physiological function of MBPs has generated significant interest in understanding the mechanisms by which these proteins read and interpret DNA methylation signals. Zinc finger and BTB domain-containing 38 (ZBTB38) represents one member of the zinc finger (ZF) family of MBPs. We recently demonstrated that the C-terminal ZFs of ZBTB38 exhibit methyl-selective DNA binding within the ((A/G)TmCG(G/A)(mC/T)(G/A)) context both in vitro and within cells. Here we report the crystal structure of the first four C-terminal ZBTB38 ZFs (ZFs 6-9) in complex with the previously identified methylated consensus sequence at 1.75 A resolution. From the structure, methyl-selective binding is preferentially localized at the 5'-mCpG site of the bound DNA which is facilitated through a series of base-specific interactions from residues within the alpha-helices of ZF7 and ZF8. ZF6 and ZF9 primarily stabilize ZF7 and ZF8 to facilitate the core base-specific interactions. Further structural and biochemical analyses, including solution NMR spectroscopy and electrophoretic mobility gel shift assays, revealed that the C-terminal ZFs of ZBTB38 utilize an alternative mode of mCpG recognition from the ZF MBPs structurally evaluated to date. Combined these findings provide insight into the mechanism by which this ZF domain of ZBTB38 selectively recognizes methylated CpG sites and expands our understanding for how ZF-containing proteins can interpret this essential epigenetic mark. Structural insights into methylated DNA recognition by the C-terminal zinc fingers of the DNA reader protein ZBTB38.,Hudson NO, Whitby FG, Buck-Koehntop BA J Biol Chem. 2018 Oct 24. pii: RA118.005147. doi: 10.1074/jbc.RA118.005147. PMID:30355731 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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