Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease
Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease
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DOI：
10.1038/emboj.2013.51
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发表时间：
2013-05-02
期刊：
影响因子：
11.4
通讯作者：
Ahel, Ivan
中科院分区：
文献类型：
--
作者：
Sharifi, Reza;Morra, Rosa;Ahel, Ivan
腺苷二磷酸（ADP）-核糖基化是一种翻译后蛋白质修饰，涉及一系列细胞过程的调节。催化ADP-核糖基化反应的蛋白质家族是聚（ADP-核糖）（PAR）聚合酶（PARP）。PARP将ADP-核糖核苷酸共价连接到靶蛋白，并且一些PARP家族成员随后可以添加额外的ADP-核糖单元以产生PAR链。PAR糖水解酶（PARG）催化PAR链的水解。PARG不能切割与蛋白质直接连接的单（ADP-核糖）单位，尽管在哺乳动物细胞提取物中检测到催化该反应的酶活性，但负责的蛋白质仍未知。在这里，我们报告了严重神经变性患者的c6 orf 130基因的纯合突变，并确定C6 orf 130作为PARP相互作用蛋白，去除单（ADP-核糖基）的谷氨酸氨基酸残基上的PARP修饰蛋白。X-射线结构和生化分析C6 orf 130建议的催化逆转涉及一个短暂的C6 orf 130赖氨酰（ADP-核糖）中间体的机制。此外，细胞中C6 orf 130蛋白的缺失导致增殖和DNA修复缺陷。总的来说，我们的数据表明，C6 orf 130酶活性在蛋白质ADP-核糖基化的周转和再循环中起作用，并且我们已经暗示了这种蛋白质在支持人类正常细胞功能中的重要性。
Adenosine diphosphate (ADP)-ribosylation is a post-translational protein modification implicated in the regulation of a range of cellular processes. A family of proteins that catalyse ADP-ribosylation reactions are the poly(ADP-ribose) (PAR) polymerases (PARPs). PARPs covalently attach an ADP-ribose nucleotide to target proteins and some PARP family members can subsequently add additional ADP-ribose units to generate a PAR chain. The hydrolysis of PAR chains is catalysed by PAR glycohydrolase (PARG). PARG is unable to cleave the mono(ADP-ribose) unit directly linked to the protein and although the enzymatic activity that catalyses this reaction has been detected in mammalian cell extracts, the protein(s) responsible remain unknown. Here, we report the homozygous mutation of the c6orf130 gene in patients with severe neurodegeneration, and identify C6orf130 as a PARP-interacting protein that removes mono(ADP-ribosyl) ation on glutamate amino acid residues in PARP-modified proteins. X-ray structures and biochemical analysis of C6orf130 suggest a mechanism of catalytic reversal involving a transient C6orf130 lysyl-(ADP-ribose) intermediate. Furthermore, depletion of C6orf130 protein in cells leads to proliferation and DNA repair defects. Collectively, our data suggest that C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP-ribosylation, and we have implicated the importance of this protein in supporting normal cellular function in humans.