title: Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2.
abstract: Methylated cytosine of CpG dinucleotides in vertebrates may be oxidized by Tet proteins, a process that can lead to DNA demethylation. The predominant oxidation product, 5-hydroxymethylcytosine (5hmC), has been implicated in embryogenesis, cell differentiation, and human diseases. Recently, the SRA domain of UHRF2 (UHRF2-SRA) has been reported to specifically recognize 5hmC, but how UHRF2 recognizes this modification is unclear. Here we report the structure of UHRF2-SRA in complex with a 5hmC-containing DNA. The structure reveals that the conformation of a phenylalanine allows the formation of an optimal 5hmC binding pocket, and a hydrogen bond between the hydroxyl group of 5hmC and UHRF2-SRA is critical for their preferential binding. Further structural and biochemical analyses unveiled the role of SRA domains as a versatile reader of modified DNA, and the knowledge should facilitate further understanding of the biological function of UHRF2 and the comprehension of DNA hydroxymethylation in general.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiong
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Wang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: rmxu@sun5.ibp.ac.cn.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Xu
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*
chemical_list: D009841:Oligonucleotides; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C465619:UHRF2 protein, human; D044767:Ubiquitin-Protein Ligases