<br>核甲基蛋白固有无序区域中核和核仁定位信号的鉴定和功能表征,Journal of Cellular Physiology

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核甲基蛋白固有无序区域中核和核仁定位信号的鉴定和功能表征
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2024-09-09 , DOI: 10.1002/jcp.31433
Akshaykumar Nanaji Shrikondawar _{1,

2} , Kiranmai Chennoju _{1,

3} , Debasish Kumar Ghosh ₄ , Akash Ranjan ₁

Affiliation

蛋白质的核仁定位受特定信号的调节，这些信号将其运输引导至细胞核和核仁。在这里，我们阐明了核甲基化素（NML）蛋白的核和核仁定位的潜在机制，重点关注其核定位信号（NLS）和核仁定位信号（NoLS）。结合生物信息学分析和实验验证，我们在 NML 中鉴定了两个单片和一个二片 NLS 基序。两种单片 NLS 的组合存在显着增强了蛋白质的核定位，而二片 NLS 中的特定碱性氨基酸簇对其功能至关重要。我们还揭示了 NLS 偶联的 NoLS 基序在驱动 NML 核仁定位中的功能作用，NML 包含对其功能至关重要的富含精氨酸的基序。NML 的 NoLS 富含精氨酸基序的碱性残基与核磷蛋白 1 （NPM1）相互作用，允许 NML 在核仁中可能的液-液相分离和保留。值得注意的是，NML 的强 NoLS 可以指导胞质蛋白醛缩酶的核仁定位，强调了其效力。总体而言，我们的研究结果为 NLS 和 NoLS 在调节 NML 亚细胞定位中的组合功能提供了见解，突出了控制其在细胞核和核仁内定位的复杂调节机制。

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Identification and functional characterization of the nuclear and nucleolar localization signals in the intrinsically disordered region of nucleomethylin

The nucleolar localization of proteins is regulated by specific signals directing their trafficking to nucleus and nucleolus. Here, we elucidate the mechanism underlying the nuclear and nucleolar localization of the nucleomethylin (NML) protein, focusing on its nuclear localization signals (NLSs) and nucleolar localization signal (NoLS). Using a combination of bioinformatic analysis and experimental validation, we identified two monopartite and one bipartite NLS motifs within NML. The combined presence of both monopartite NLSs significantly enhances nuclear localization of the protein, while specific basic amino acid clusters within the bipartite NLS are crucial for their functionality. We also reveal the functional role of the NLS‐coupled NoLS motif in driving nucleolar localization of NML, which contains an arginine‐rich motif essential for its function. The basic residues of the arginine‐rich motif of NoLS of NML interacts with nucleophosmin 1 (NPM1), allowing the possible liquid‐liquid phase separation and retention of NML in the nucleolus. Remarkably, the strong NoLS of NML can direct the nucleolar localization of a cytosolic protein, aldolase, emphasizing its potency. Overall, our findings provide insights into the combinatorial functioning of NLSs and NoLS in regulating the subcellular localization of NML, highlighting the intricate regulatory mechanisms governing its localization within the nucleus and nucleolus.

更新日期：2024-09-09

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