对 NIMA 相关激酶 6 的计算洞察:揭示突变对结构和功能的影响。

IF 3.5 2区 生物学 Q3 CELL BIOLOGY Molecular and Cellular Biochemistry Pub Date : 2024-11-01 Epub Date: 2023-12-20 DOI:10.1007/s11010-023-04910-0
Nagesh Kishan Panchal, Shruti Mohanty, Sabina Evan Prince
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引用次数: 0

摘要

NEK6(NIMA 相关激酶 6)丝氨酸/苏氨酸激酶在多种细胞过程中起着关键作用,包括调节细胞周期和应对 DNA 损伤。NEK6 活性的变化与癌症的发生有关,因此它的意义还延伸到疾病的发病机制。NEK6 中的非同义单核苷酸多态性(nsSNPs)与癌症有关,因为它们会改变蛋白质的原生结构和功能。NEK6 活性与癌症发展之间的关联促使研究人员探索 NEK6 基因内部遗传变异的影响。因此,我们利用先进的计算工具分析了 NEK6 基因中的 155 个高置信度 nsSNPs。通过分析,我们发现 21 个 nsSNPs 可能是有害的,这引起了我们对它们对 NEK6 活性和癌症风险影响的关注。然后对这 21 个突变进行了结构改变检测,发现其中 8 个 nsSNPs(I51M、V76A、I134N、Y152D、R171Q、V186G、L237R 和 C285S)会破坏蛋白质的稳定性。在筛选出的脱稳突变中,R171Q 突变因其保守性而脱颖而出。为了了解它对蛋白质和构象的影响,我们对野生型 NEK6(WT-NEK6)和 R171Q 进行了 100 ns 的全原子分子动力学模拟(MDS)。模拟结果表明,R171Q 变体并不稳定,会导致 NEK6 发生显著的构象变化。这项研究为了解单个氨基酸改变导致的 NEK6 功能障碍提供了宝贵的见解,为了解 NEK6 相关癌症进展的分子机制提供了新的视角。
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Computational insights into NIMA-related kinase 6: unraveling mutational effects on structure and function.

The NEK6 (NIMA-related kinase 6) serine/threonine kinase is a pivotal player in a multitude of cellular processes, including the regulation of the cell cycle and the response to DNA damage. Its significance extends to disease pathogenesis, as changes in NEK6 activity have been linked to the development of cancer. Non-synonymous single nucleotide polymorphisms (nsSNPs) in NEK6 have been linked to cancer as they alter the protein's native structure and function. The association between NEK6 activity and cancer development has prompted researchers to explore the effects of genetic variations within the NEK6 gene. Therefore, we utilized advanced computational tools to analyze 155 high-confidence nsSNPs in the NEK6 gene. From this analysis, 21 nsSNPs were identified as potentially harmful, raising concerns about their impact on NEK6 activity and cancer risk. These 21 mutations were then examined for structural alterations, and eight of nsSNPs (I51M, V76A, I134N, Y152D, R171Q, V186G, L237R, and C285S) were found to destabilize the protein. Among the destabilizing mutations screened, a specific mutation, R171Q, stood out due to its conserved nature. To understand its impact on the protein and conformation, all-atom molecular dynamics simulations (MDS) for 100 ns were performed for both Wildtype NEK6 (WT-NEK6) and R171Q. The simulations revealed that the R171Q variant was unstable and led to significant conformational changes in NEK6. This study provides valuable insights into NEK6 dysfunction caused by single amino acid alterations, offering a novel understanding of the molecular mechanisms underlying NEK6-related cancer progression.

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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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