Structural insights into a novel histone demethylase PHF8  

作　　者：Lin Yu Yang wang Shuo Huang Jianjun Wang Zengqin Deng Qi Zhang Wei Wu Xingliang Zhang Zhao Liu Weimin Gong Zhongzhou Chen 

机构地区：[1]State Key Laboratory of Agrobio Wchnology College of Biological Sciences, China Agricultural University, Beijing 100193, China [2]Department of Biochemistry and Molecular Biology, National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China [3]State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China

出　　处：《Cell Research》2010年第2期166-173,共8页细胞研究（英文版）

基　　金：Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Dr Dawei Li （China Agricultural University） for generously providing us with the experimental conditions during the early stages of this project. We thank Dr Ruiming Xu （Institute of Biophysics, Chinese Academy of Sciences） for critical reading of this manuscript and advice. We thank Dr Pinchao Mei （Chinese Academy of Medical Sciences and Peking Union Medical College）, Xinqi Liu （Nankai University） and Jiemin Wong （East China Normal University） for discussions and advice. The synchrotronradiation experiments were performed at Shanghai Synchrotron Radiation Facility （SSRF） and NE3A in the Photon Factory. Z.C. is supported by the National Basic Research Program of China （973 Program, 2009CB825501）, the National Natural Science Foundation of China （30870494 and 90919043）, the New Century Excellent Talents in University （NCET-07-0808） and the Innovative Project of SKLAB. S. H. is supported by the National Key Laboratory Special Fund 2060204. Z. D. is supported by the National Natural Science Foundation of China （J0730639）.

摘　　要：Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.

关 键 词：PHF8 （PHD finger protein 8） histone demethylase chromatin modification methylated H3K9 crystal structure X-linked mental retardation （XLMR） facial anomalies 

分 类 号：Q52[生物学—生物化学] Q949.329