Bordet Guillaume, Karpova Yaroslava, Espeseth Saraynia, Mitzel Gavin, Bigelow Zachary, Tulin Alexei V
Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Road, Stop 9061, Grand Forks, ND 58202, USA.
Int J Mol Sci. 2025 Aug 22;26(17):8166. doi: 10.3390/ijms26178166.
Intrinsically disordered regions (IDRs) are present in nearly all proteins, often accounting for more than 40% of their amino acid sequence. Unlike structured domains, IDRs lack sequence or structural conservation across species while maintaining conserved biological functions. Here, we discovered that the previously uncharacterized disordered tail region of Poly(ADP-ribose) glycohydrolase (PARG) controls its localization and activity. Despite its structural divergence, this domain supports conserved regulatory functions across species. Deletion of the disordered tail results in cytoplasmic mislocalization, aberrant accumulation in the nucleolus, impaired chromatin association, and reduced enzymatic activity. Mass spectrometry analysis reveals that this disordered region mediates interactions with nuclear transport factors, post-translational modification enzymes, and chromatin-associated complexes. Together, these results demonstrate that the disordered tail region of PARG acts as a regulatory hub that integrates multiple layers of control to ensure proper subcellular localization and chromatin function.
内在无序区域（IDRs）几乎存在于所有蛋白质中，通常占其氨基酸序列的40%以上。与结构化结构域不同，IDRs在物种间缺乏序列或结构保守性，但能维持保守的生物学功能。在此，我们发现聚（ADP - 核糖）糖苷水解酶（PARG）先前未被表征的无序尾部区域控制着其定位和活性。尽管该结构域在结构上存在差异，但它在物种间支持保守的调节功能。无序尾部的缺失会导致细胞质定位错误、在核仁中异常积累、染色质结合受损以及酶活性降低。质谱分析表明，这个无序区域介导了与核转运因子、翻译后修饰酶以及染色质相关复合物的相互作用。这些结果共同表明，PARG的无序尾部区域作为一个调节枢纽，整合了多层控制以确保正确的亚细胞定位和染色质功能。
