The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases.

The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases.
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DOI:
10.1038/s41589-018-0071-y
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发表时间:
2018-07
影响因子:
14.8
通讯作者:
Schofield CJ
Schofield CJ
中科院分区:
生物学1区
文献类型:
--
作者:
Markolovic S;Zhuang Q;Wilkins SE;Eaton CD;Abboud MI;Katz MJ;McNeil HE;Leśniak RK;Hall C;Struwe WB;Konietzny R;Davis S;Yang M;Ge W;Benesch JLP;Kessler BM;Ratcliffe PJ;Cockman ME;Fischer R;Wappner P;Chowdhury R;Coleman ML;Schofield CJ

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生物化学、结构和细胞研究揭示了Jumonji-C(JmjC)结构域7(JMJD 7)作为2-酮戊二酸(2 OG)依赖性加氧酶催化先前未报道的翻译后修饰类型(3S)-赖氨酰羟基化。晶体学分析揭示JMJD 7与JmjC羟化酶而不是与JmjC脱甲基酶更密切相关。生物物理和突变研究表明,JMJD 7具有独特的二聚化模式,单体之间的相互作用涉及N-和C-末端区域和二硫键形成。蛋白质组学方法鉴定了GTP酶的翻译因子(TRAFAC)家族的两个相关成员,发育调节的GTP结合蛋白1和2(DRG 1/2),作为活性依赖性JMJD 7相互作用物。质谱分析表明JMJD 7催化DRG 1/2中高度保守的赖氨酸残基的Fe(II)-和2 OG-依赖性羟基化;氨基酸分析揭示JMJD 7催化(3S)-赖氨酰羟基化。JMJD 7的功能分配将使未来的研究能够确定DRG羟基化在细胞生长和疾病中的作用。
Biochemical, structural, and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) as a 2-oxoglutarate (2OG)-dependent oxygenase catalyzing a previously unreported type of post-translational modification, (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 as more closely related to the JmjC hydroxylases rather than the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the Translation Factor (TRAFAC) family of GTPases, Developmentally Regulated GTP Binding Proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(II)- and 2OG-dependent hydroxylation of a highly-conserved lysine residue in DRG1/2; amino acid analyses reveal JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.
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