Structural insights into a novel histone demethylase PHF8.
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 alpha-ketoglutarate (alpha-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.
Yu
Lin
L
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Wang
Yang
Y
Huang
Shuo
S
Wang
Jianjun
J
Deng
Zengqin
Z
Zhang
Qi
Q
Wu
Wei
W
Zhang
Xingliang
X
Liu
Zhao
Z
Gong
Weimin
W
Chen
Zhongzhou
Z
D020134:Catalytic Domain; D018389:Codon, Nonsense / Q000502:physiology; D004789:Enzyme Activation; D006367:HeLa Cells; D056466:Histone Demethylases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009422:Nervous System Diseases / Q000235:genetics; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D018389:Codon, Nonsense; D006657:Histones; D050505:Mutant Proteins; D014157:Transcription Factors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C511934:PHF8 protein, human; D008239:Lysine