人UHRF1的SRA结构域的结构与半甲基化CpG结合
Structure and hemimethylated CpG binding of the SRA domain from human UHRF1.
作者信息
Qian Chengmin, Li Side, Jakoncic Jean, Zeng Lei, Walsh Martin J, Zhou Ming-Ming
机构信息
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York University, New York, New York 10029, USA.
出版信息
J Biol Chem. 2008 Dec 12;283(50):34490-4. doi: 10.1074/jbc.C800169200. Epub 2008 Oct 22.
Abstract
Human UHRF1 (ubiquitin-like PHD and RING finger 1) functions to maintain CpG DNA methylation patterns through DNA replication by co-localizing with the DNA methyltransferase DNMT1 at chromatin in mammals. Recent studies show that UHRF1 binds selectively to hemimethylated CpG via its conserved SRA (SET- and RING finger-associated) domain. However, the underlying molecular mechanism is not known. Here, we report a 1.95 A resolution crystal structure of the SRA domain of human UHRF1. Using NMR structure-guided mutagenesis, electrophoretic mobility shift assay, and fluorescence anisotropy analysis, we determined key amino acid residues for methyl-DNA binding that are conserved in the SRA domain.
摘要
人类UHRF1（泛素样PHD和RING指蛋白1）通过在哺乳动物染色质上与DNA甲基转移酶DNMT1共定位，在DNA复制过程中维持CpG DNA甲基化模式。最近的研究表明，UHRF1通过其保守的SRA（SET和RING指相关）结构域选择性地结合半甲基化的CpG。然而，其潜在的分子机制尚不清楚。在这里，我们报道了人类UHRF1的SRA结构域分辨率为1.95埃的晶体结构。通过核磁共振结构引导的诱变、电泳迁移率变动分析和荧光各向异性分析，我们确定了SRA结构域中保守的甲基化DNA结合关键氨基酸残基。
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本文引用的文献
1
Processing of X-ray diffraction data collected in oscillation mode.振荡模式下收集的X射线衍射数据的处理。
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
2
The PHD domain of Np95 (mUHRF1) is involved in large-scale reorganization of pericentromeric heterochromatin.Np95（小鼠泛素样含PHD和RING结构域的蛋白质1）的PHD结构域参与着丝粒周围异染色质的大规模重组。
Mol Biol Cell. 2008 Aug;19(8):3554-63. doi: 10.1091/mbc.e07-10-1059. Epub 2008 May 28.
3
MeCP2 binding to DNA depends upon hydration at methyl-CpG.MeCP2与DNA的结合取决于甲基化CpG处的水化作用。
Mol Cell. 2008 Feb 29;29(4):525-31. doi: 10.1016/j.molcel.2007.12.028.
4
The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA.SRA蛋白Np95通过将Dnmt1招募至甲基化DNA来介导表观遗传继承。
Nature. 2007 Dec 6;450(7171):908-12. doi: 10.1038/nature06397. Epub 2007 Nov 11.
5
ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation.ICBP90，一种将蛋白质泛素化与异染色质形成联系起来的新型甲基化K9组蛋白H3结合蛋白。
Mol Cell Biol. 2008 Jan;28(2):705-17. doi: 10.1128/MCB.01598-07. Epub 2007 Oct 29.
6
The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression.ICBP90的SRA结构域与DNMT1的一个新结构域之间的相互作用参与了VEGF基因表达的调控。
Oncogene. 2008 Apr 3;27(15):2187-97. doi: 10.1038/sj.onc.1210855. Epub 2007 Oct 15.
7
Plant SET- and RING-associated domain proteins in heterochromatinization.植物中与异染色质化相关的SET和RING结构域蛋白。
Plant J. 2007 Dec;52(5):914-26. doi: 10.1111/j.1365-313X.2007.03286.x. Epub 2007 Sep 22.
8
UHRF1 plays a role in maintaining DNA methylation in mammalian cells.UHRF1在维持哺乳动物细胞中的DNA甲基化方面发挥作用。
Science. 2007 Sep 21;317(5845):1760-4. doi: 10.1126/science.1147939. Epub 2007 Aug 2.
9
The UHRF family: oncogenes that are drugable targets for cancer therapy in the near future?UHRF家族：在不久的将来有望成为癌症治疗中可靶向用药的癌基因？
Pharmacol Ther. 2007 Sep;115(3):419-34. doi: 10.1016/j.pharmthera.2007.06.003. Epub 2007 Jun 22.
10
The mammalian epigenome.哺乳动物表观基因组。
Cell. 2007 Feb 23;128(4):669-81. doi: 10.1016/j.cell.2007.01.033.
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