期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
卷 1862, 期 9, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbagrm.2019.194409
关键词
MeCP2; MARs; Non-CG methylated DNA; GTG containing DNA; X-ray crystallography; Rett syndrome
资金
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- DOE Office of Science [DE-AC02-06CH11357]
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- University of Saskatchewan
- Government of Saskatchewan
- Western Economic Diversification Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- Howard Hughes Medical Institute
- Department of Energy Office of Science User Facility [DE-AC02-05CH11231]
- NIH [S10OD021832]
- National Institutes of Health, National Institute of General Medical Sciences [P30 GM124169]
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Canada Foundation for Innovation, Eshelman Institute for Innovation [1097737]
- Genome Canada through Ontario Genomics Institute [1097737, OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA, Darmstadt, Germany [1097737]
- Boehringer Ingelheim [1097737]
- Eshelman Institute for Innovation [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Research, Innovation and Science (MRIS) [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome [1097737]
MeCP2 is an abundant protein, involved in transcriptional repression by binding to CG and non-CG methylated DNA. However, MeCP2 might also function as a transcription activator as MeCP2 is found bound to sparsely methylated promoters of actively expressed genes. Furthermore, Attachment Region Binding Protein (ARBP), the chicken ortholog of MeCP2, has been reported to bind to Matrix/scaffold attachment regions (MARs/SARs) DNA with an unmethylated 5'-CAC/GTG-3' consensus sequence. In our previous study, although we have systemically measured the binding abilities of MBDs to unmethylated CAC/GTG DNA and the complex structures reveal that the MBD2-MBD (MBD of MBD2) binds to the unmethylated CAC/GTG DNA by recognizing the complementary GTG trinucleotide, how the MeCP2-MBD (MBD of MeCP2) recognizes the unmethylated CAC/GTG DNA, especially the MARs DNA, is still unclear. In this study, we investigated the binding characteristics of MeCP2 in recognizing unmethylated 5'-CAC/GTG-3' motif containing DNA by binding and structural studies. We found that MeCP2-MBD binds to MARs DNA with a comparable binding affinity to mCG DNA, and the MeCP2-CAC/GTG complex structure revealed that MeCP2 residues R111 and R133 form base-specific interactions with the GTG motif. For comparison, we also determined crystal structures of the MeCP2-MBD bound to mCG and mCAC/GTG DNA, respectively. Together, these crystal structures illustrate the adaptability of the MeCP2-MBD toward the GTG motif as well as the mCG DNA, and also provide structural basis of a biological role of MeCP2 as a transcription activator and its disease implications in Rett syndrome.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据