Structural and Functional Insights into the Human Borjeson- Forssman- Lehmann Syndrome- associated Protein PHF6*
Structural and Functional Insights into the Human Borjeson- Forssman- Lehmann Syndrome- associated Protein PHF6*
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人类 Borjeson-Forssman-Lehmann 综合征相关蛋白 PHF6 的结构和功能见解
DOI：
10.1074/jbc.m113.535351
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
Shi, Yunyu
中科院分区：
文献类型：
--
作者：
Liu, Zhonghua;Li, Fudong;Shi, Yunyu
背景：PHF 6基因在BFLS、成人急性髓细胞白血病和T细胞急性淋巴细胞白血病中存在突变。结果：解析了PHF 6第二延伸PHD结构域的晶体结构。结论：PHF 6-ePHD 2是一个新的结构模块，能与dsDNA结合。重要性：PHF 6是一个转录抑制因子，其ePHD结构域与DNA结合，通过NoLS区募集NuRD复合物来调节基因转录，PHF 6最初被鉴定为X连锁智力低下疾病Borjeson-Forssman-Lehmann综合征中的突变基因。PHF 6基因的突变也与T细胞急性淋巴细胞白血病和急性髓细胞白血病有关。大约一半的疾病相关突变分布在PHF 6的第二个保守的扩展植物同源结构域（ePHD 2）中，表明ePHD 2结构域的功能重要性。在这里，我们报告了PHF 6的ePHD 2结构域的高分辨率晶体结构，其中包含N-末端前PHD（C2 HC锌指），长接头和非典型PHD指。PHF 6-ePHD 2似乎作为一种新的整合结构模块折叠。PHF 6-ePHD 2的结构分析揭示了PHF 6基因突变在Borjeson-Forssman-Lehmann综合征、T细胞急性淋巴细胞白血病和急性髓性白血病中的病理意义。结合实验表明PHF 6-ePHD 2能与dsDNA结合，但不能与组蛋白结合。我们还证明PHF 6蛋白直接与核小体重塑和脱乙酰化复合物组分RBBP 4相互作用。通过这种相互作用，PHF 6发挥其转录抑制活性。总之，这些数据支持的假设，PHF 6可能作为一个转录阻遏物使用其ePHD结构域结合到其抑制基因的启动子区，这一过程是由核小体重塑和脱乙酰化复合物，募集到基因组靶位点的PHF 6的NoLS区域的调节。
Background:PHF6 gene is mutated in BFLS and adult acute myeloid and T-cell acute lymphoblastic leukemias. Results: Crystal structure of the second extended PHD domain of PHF6 was solved. Conclusion: PHF6-ePHD2 is a novel structural module and binds dsDNA. Significance: PHF6 may function as a transcriptional repressor using its ePHD domains binding to DNA and recruiting NuRD complex through its NoLS region to regulate gene transcription.The plant homeodomain finger 6 (PHF6) was originally identified as the gene mutated in the X-linked mental retardation disorder Borjeson-Forssman-Lehmann syndrome. Mutations in the PHF6 gene have also been associated with T-cell acute lymphoblastic leukemia and acute myeloid leukemia. Approximately half of the disease-associated mutations are distributed in the second conserved extended plant homeodomain (ePHD2) of PHF6, indicating the functional importance of the ePHD2 domain. Here, we report the high resolution crystal structure of the ePHD2 domain of PHF6, which contains an N-terminal pre-PHD (C2HC zinc finger), a long linker, and an atypical PHD finger. PHF6-ePHD2 appears to fold as a novel integrated structural module. Structural analysis of PHF6-ePHD2 reveals pathological implication of PHF6 gene mutations in Borjeson-Forssman-Lehmann syndrome, T-cell acute lymphoblastic leukemia, and acute myeloid leukemia. The binding experiments show that PHF6-ePHD2 can bind dsDNA but not histones. We also demonstrate PHF6 protein directly interacts with the nucleosome remodeling and deacetylation complex component RBBP4. Via this interaction, PHF6 exerts its transcriptional repression activity. Taken together, these data support the hypothesis that PHF6 may function as a transcriptional repressor using its ePHD domains binding to the promoter region of its repressed gene, and this process was regulated by the nucleosome remodeling and deacetylation complex that was recruited to the genomic target site by NoLS region of PHF6.